Biological Applications of Thiourea Derivatives: Detailed Review

: Thiourea and its derivatives have become a significant focal point within the organic synthesis field, garnering attention for their diverse biological applications, including antibacterial, antioxidant, anticancer, anti-inflammatory, anti-Alzheimer, antituberculosis and antimalarial properties. My objective is to present a comprehensive and easily understandable analysis of recent advancements in the organic synthesis of thiourea derivatives. My focus is on the structure and activity of these derivatives over the past five years, highlighting the significant progress made in the field of organic synthesis. Additionally, I evaluate the current state of research in this area and provide an overview of the latest trends and future prospects. This review will prove to be beneficial for researchers, academics and industry professionals involved in drug development and organic synthesis.


Introduction
Thiourea is an organosulfur compound with a chemical formula of SC(NH 2 ) 2 , and its structure is represented in Figure 1.Its structure is similar to that of urea (H 2 N-C(=O)-NH 2 ), except the oxygen atom is replaced by a sulfur atom, indicated by the prefix "thio-" [1].The term "thiourea" refers to a group of compounds with the formula (R 1 R 2 N) (R 3 R 4 N) C=S.Thiourea has two tautomeric forms: the thione form and the thiol form, as illustrated in Figure 2. The thione form is more prevalent in aqueous solutions, and the thiol form is also known as isothiourea.

Introduction
Thiourea is an organosulfur compound with a chemical formula of SC(NH2)2, and its structure is represented in Figure 1.Its structure is similar to that of urea (H2N-C(=O)-NH2), except the oxygen atom is replaced by a sulfur atom, indicated by the prefix "thio-" [1].The term "thiourea" refers to a group of compounds with the formula (R1R2N) (R3R4N) C=S.Thiourea has two tautomeric forms: the thione form and the thiol form, as illustrated in Figure 2. The thione form is more prevalent in aqueous solutions, and the thiol form is also known as isothiourea.
Thiourea has a wide range of uses in organic synthesis reactions as intermediates making it an incredibly versatile compound [2].Additionally, it is utilized in many commercial products such as photographic films, dyes, elastomers, plastics and textiles [3].However, the most significant and effective application of thiourea is in the realm of biology as illustrated in Figure 3. Research has demonstrated that it possesses numerous beneficial properties, including antibacterial, antioxidant, anticancer, anti-inflammatory, anti-Alzheimer, antitubercular and antimalarial effects [4][5][6][7][8][9].Several previous reviews have focused on the pharmacological activities of thiourea derivatives [10][11][12].Here, this review presents an overview of state-of-the-art biomolecules derived from thiourea as well as diverse medicinal applications in this field over the last five years.Thiourea has a wide range of uses in organic synthesis reactions as intermediates, making it an incredibly versatile compound [2].Additionally, it is utilized in many commercial products such as photographic films, dyes, elastomers, plastics and textiles [3].However, the most significant and effective application of thiourea is in the realm of biology, as illustrated in Figure 3. Research has demonstrated that it possesses numerous beneficial properties, including antibacterial, antioxidant, anticancer, anti-inflammatory, anti-Alzheimer, antitubercular and antimalarial effects [4][5][6][7][8][9].Several previous reviews have focused on the pharmacological activities of thiourea derivatives [10][11][12].Here, this review presents an overview of state-of-the-art biomolecules derived from thiourea as well as diverse medicinal applications in this field over the last five years.

Antibacterial Activity
The lack of new anti-infective drugs is a major concern for medicinal chemistry, as antimicrobial resistance poses a global threat.In response, Sumaira et al. [13] developed novel thiourea derivatives using amine derivatives as nucleophiles on the electrophilic carbon of CS2 to synthesize a thiocarbamate intermediate, as shown in Scheme 1.Both compounds 1 and 2 demonstrated antibacterial activity against E. faecalis, P. aeruginosa, S. typhi and K. pneumoniae.Compound 2 exhibited greater potency than that of compound 1, with a minimum inhibitory concentration (MIC) against the tested organism ranging from 40 to 50 µg/mL.In comparison to the standard antibiotic, ceftriaxone, compound 2 showed comparable inhibition zone diameters.The inhibition zones of compound 2 against the tested organisms were 29, 24, 30 and 19 mm, respectively.

Antibacterial Activity
The lack of new anti-infective drugs is a major concern for medicinal chemistry, as antimicrobial resistance poses a global threat.In response, Sumaira et al. [13] developed novel thiourea derivatives using amine derivatives as nucleophiles on the electrophilic carbon of CS2 to synthesize a thiocarbamate intermediate, as shown in Scheme 1.Both compounds 1 and 2 demonstrated antibacterial activity against E. faecalis, P. aeruginosa, S. typhi and K. pneumoniae.Compound 2 exhibited greater potency than that of compound 1, with a minimum inhibitory concentration (MIC) against the tested organism ranging from 40 to 50 µg/mL.In comparison to the standard antibiotic, ceftriaxone, compound 2 showed comparable inhibition zone diameters.The inhibition zones of compound 2 against the tested organisms were 29, 24, 30 and 19 mm, respectively.hemistry 2024, 6, FOR PEER REVIEW 3 Scheme 1.The general mechanism of thiourea derivative synthesis starting with carbon disulfide [13].

2
A novel set of seven N-acyl thiourea derivatives, namely 3a-3g, were developed by Roxana et al. [14].Their synthesis method employed the condensation of acid chloride and ammonium thiocyanate in an anhydrous acetone solution.The resulting isocyanate was then allowed to react with a heterocyclic amine, with the amine undergoing a nucleophilic addition to the isocyanate, as shown in Scheme 2.
The synthesized compounds, 3a-3g, were subjected to testing against various bacte-Scheme 1.The general mechanism of thiourea derivative synthesis starting with carbon disulfide [13].
Chemistry 2024, 6, FOR PEER REVIEW 3 Scheme 1.The general mechanism of thiourea derivative synthesis starting with carbon disulfide [13].

2
A novel set of seven N-acyl thiourea derivatives, namely 3a-3g, were developed by Roxana et al. [14].Their synthesis method employed the condensation of acid chloride and ammonium thiocyanate in an anhydrous acetone solution.The resulting isocyanate was then allowed to react with a heterocyclic amine, with the amine undergoing a nucleophilic addition to the isocyanate, as shown in Scheme 2.
The synthesized compounds, 3a-3g, were subjected to testing against various bacterial strains, including S. aureus, E. faecalis, E. coli and P. aeruginosa.The positive control used was Ciprofloxacin (5 µg/mL).The findings demonstrated that the tested drugs' MIC ranged from >5000 to 1250 µg/mL, which was considerably greater than the conventional A novel set of seven N-acyl thiourea derivatives, namely 3a-3g, were developed by Roxana et al. [14].Their synthesis method employed the condensation of acid chloride and ammonium thiocyanate in an anhydrous acetone solution.The resulting isocyanate was then allowed to react with a heterocyclic amine, with the amine undergoing a nucleophilic addition to the isocyanate, as shown in Scheme 2.
OR PEER REVIEW 3 Scheme 1.The general mechanism of thiourea derivative synthesis starting with carbon disulfide [13].

2
A novel set of seven N-acyl thiourea derivatives, namely 3a-3g, were developed by Roxana et al. [14].Their synthesis method employed the condensation of acid chloride and ammonium thiocyanate in an anhydrous acetone solution.The resulting isocyanate was then allowed to react with a heterocyclic amine, with the amine undergoing a nucleophilic addition to the isocyanate, as shown in Scheme 2.
The synthesized compounds, 3a-3g, were subjected to testing against various bacterial strains, including S. aureus, E. faecalis, E. coli and P. aeruginosa.The positive control used was Ciprofloxacin (5 µg/mL).The findings demonstrated that the tested drugs' MIC Scheme 2. The synthesis route of novel N-acyl thiourea derivatives 3a-3g [14].
The synthesized compounds, 3a-3g, were subjected to testing against various bacterial strains, including S. aureus, E. faecalis, E. coli and P. aeruginosa.The positive control used was Ciprofloxacin (5 µg/mL).The findings demonstrated that the tested drugs' MIC ranged from >5000 to 1250 µg/mL, which was considerably greater than the conventional antibiotic utilized.These compounds were found to be more potent than previously reported thiazole derivatives [14].In addition, eight tris-thiourea derivatives, 4a-4h, with symmetrical structures, were synthesized using benzoyl chloride and potassium thiocyanate with melamine under reflux conditions through a condensation reaction.The synthesis pathway is depicted in Scheme 3 [15].istry 2024, 6, FOR PEER REVIEW antibiotic utilized.These compounds were found to be more potent than previously ported thiazole derivatives [14].In addition, eight tris-thiourea derivatives, 4a-4h, w symmetrical structures, were synthesized using benzoyl chloride and potassium thiocy nate with melamine under reflux conditions through a condensation reaction.The synth sis pathway is depicted in Scheme 3 [15].Thiourea derivatives are highly effective in metal complexes due to the presence nitrogen atoms, as well as lone pairs on sulfur and oxygen atoms, which serve as ligati centers and coordinate with a wide range of metal centers to produce stable metal co plexes [16].Ahmed et al. synthesized novel 1-morpholinyl 3-phenyl thiourea ligands a their corresponding metal complexes with the aim of developing new antimicrob agents.The ligand N-Phenylmorpholine-4-carbothioamide (HPMCT) was prepared cording to the procedure outlined in Scheme 4 [17].
In complexes 5-8, the thiourea ligand coordinates through a sulfur atom as a monode tate, as demonstrated in Scheme 5 [17].On the other hand, in complexes 9-15, the ligand Scheme 3. Synthesis pathway of tris-thiourea derivatives 4a-4h [15].Thiourea derivatives are highly effective in metal complexes due to the presence of nitrogen atoms, as well as lone pairs on sulfur and oxygen atoms, which serve as ligating centers and coordinate with a wide range of metal centers to produce stable metal complexes [16].Ahmed et al. synthesized novel 1-morpholinyl 3-phenyl thiourea ligands and their corresponding metal complexes with the aim of developing new antimicrobial agents.The ligand N-Phenylmorpholine-4-carbothioamide (HPMCT) was prepared according to the procedure outlined in Scheme 4 [17].
Chemistry 2024, 6, FOR PEER REVIEW 4 antibiotic utilized.These compounds were found to be more potent than previously reported thiazole derivatives [14].In addition, eight tris-thiourea derivatives, 4a-4h, with symmetrical structures, were synthesized using benzoyl chloride and potassium thiocyanate with melamine under reflux conditions through a condensation reaction.The synthesis pathway is depicted in Scheme 3 [15].Thiourea derivatives are highly effective in metal complexes due to the presence of nitrogen atoms, as well as lone pairs on sulfur and oxygen atoms, which serve as ligating centers and coordinate with a wide range of metal centers to produce stable metal complexes [16].Ahmed et al. synthesized novel 1-morpholinyl 3-phenyl thiourea ligands and their corresponding metal complexes with the aim of developing new antimicrobial agents.The ligand N-Phenylmorpholine-4-carbothioamide (HPMCT) was prepared according to the procedure outlined in Scheme 4 [17].Scheme 4. Preparation of N-Phenylmorpholine-4-carbothioamide (HPMCT) ligand [17].
In complexes 5-8, the thiourea ligand coordinates through a sulfur atom as a monodentate, as demonstrated in Scheme 5 [17].On the other hand, in complexes 9-15, the ligand coordinates with the central atom through N and S atoms as a bidentate, as shown in Scheme 6.In complexes 5-8, the thiourea ligand coordinates through a sulfur atom as a monodentate, as demonstrated in Scheme 5 [17].On the other hand, in complexes 9-15, the ligand coordinates with the central atom through N and S atoms as a bidentate, as shown in Scheme 6.
Three strains of bacteria "E.coli, S. aureus, and K. pneumoniae" were used to test each of the produced compounds, 5-15.As seen in Figure 4 [17], all compounds exhibited strong antibacterial activity when compared to the ligand.Comparable to the common antibiotic tetracycline, compounds 5 and 9 had strong efficacy against E. coli.The several binding modes with the essential amino acid residues of the bacterial tyrosinase enzyme's active site are referred to as the antibacterial activity.Three strains of bacteria "E.coli, S. aureus, and K. pneumoniae" were used to test each of the produced compounds, 5-15.As seen in Figure 4 [17], all compounds exhibited strong antibacterial activity when compared to the ligand.Comparable to the common antibiotic tetracycline, compounds 5 and 9 had strong efficacy against E. coli.The several binding modes with the essential amino acid residues of the bacterial tyrosinase enzyme's active site are referred to as the antibacterial activity.Scheme 6. Synthesis of complexes 9-15 of thiourea derivatives [17].
Three strains of bacteria "E.coli, S. aureus, and K. pneumoniae" were used to test each of the produced compounds, 5-15.As seen in Figure 4 [17], all compounds exhibited strong antibacterial activity when compared to the ligand.Comparable to the common antibiotic tetracycline, compounds 5 and 9 had strong efficacy against E. coli.The several binding modes with the essential amino acid residues of the bacterial tyrosinase enzyme's active site are referred to as the antibacterial activity.Five new Cu (II) complexes, Cu16-Cu20, with varied antimicrobial activities, were synthesized by Aleksandra et al. [18].Five distinct ligands were produced and employed prior to complex formation.The particular groups of the ligands made of thiourea derivatives determine how copper complexes with them.Ligands 19 and 20 were halogen phenyl groups, and ligands 16-18 were alkylphenyl [19][20][21].The method for synthesis is shown in Figure 5   Five new Cu (II) complexes, Cu16-Cu20, with varied antimicrobial activities, were synthesized by Aleksandra et al. [18].Five distinct ligands were produced and employed prior to complex formation.The particular groups of the ligands made of thiourea derivatives determine how copper complexes with them.Ligands 19 and 20 were halogen phenyl groups, and ligands 16-18 were alkylphenyl [19][20][21].The method for synthesis is shown in  Five new Cu (II) complexes, Cu16-Cu20, with varied antimicrobial activities, were synthesized by Aleksandra et al. [18].Five distinct ligands were produced and employed prior to complex formation.The particular groups of the ligands made of thiourea derivatives determine how copper complexes with them.Ligands 19 and 20 were halogen phenyl groups, and ligands 16-18 were alkylphenyl [19][20][21].The method for synthesis is shown in Figure 5

21
Ten novel thiourea derivatives, 22-31, were recently synthesized by sium thiocyanate with 4-methoxy benzoyl chloride using the nucleophilic ination mechanism to form an isothiocyanate derivative, as shown in Sch final ten compounds were produced by reacting this derivative with var accordance with the amine's nucleophilic addition mechanism to the isoth DPPH radical scavenging activity method was used to describe these com sess their antioxidant potential.Compounds 29, 27 and 24 demonstrated go activity with IC50 values of 5.8, 42.3 and 45 µg/mL, respectively, when comp ascorbic acid, which had an IC50 value of −33.22 µg/mL.The other drugs' IC between 89 and 245 µg/mL.Scheme 7. Synthesis of new thiourea derivatives 22−31 through nucleophilic add mechanism [24].
Ten novel thiourea derivatives, 22-31, were recently synthesized by reacting potassium thiocyanate with 4-methoxy benzoyl chloride using the nucleophilic addition-elimination mechanism to form an isothiocyanate derivative, as shown in Scheme 7 [24].The final ten compounds were produced by reacting this derivative with various amines in accordance with the amine's nucleophilic addition mechanism to the isothiocyanate.The DPPH radical scavenging activity method was used to describe these compounds and assess their antioxidant potential.Compounds 29, 27 and 24 demonstrated good antioxidant activity with IC 50 values of 5.8, 42.3 and 45 µg/mL, respectively, when compared to normal ascorbic acid, which had an IC 50 value of −33.22 µg/mL.The other drugs' IC 50 values varied between 89 and 245 µg/mL.

21
Ten novel thiourea derivatives, 22-31, were recently synthesized by reacting potassium thiocyanate with 4-methoxy benzoyl chloride using the nucleophilic addition-elimination mechanism to form an isothiocyanate derivative, as shown in Scheme 7 [24].The final ten compounds were produced by reacting this derivative with various amines in accordance with the amine's nucleophilic addition mechanism to the isothiocyanate.The DPPH radical scavenging activity method was used to describe these compounds and assess their antioxidant potential.Compounds 29, 27 and 24 demonstrated good antioxidant activity with IC50 values of 5.8, 42.3 and 45 µg/mL, respectively, when compared to normal ascorbic acid, which had an IC50 value of −33.22 µg/mL.The other drugs' IC50 values varied between 89 and 245 µg/mL.

Anticancer Activity
In the fight against cancer, thiourea derivatives have demonstrated great promise.Studies conducted recently have demonstrated that these compounds can inhibit the growth of several cancer cell lines and reverse treatment resistance in cancer cells [25][26][27][28][29][30].A variety of human cell lines, including those from breast and lung malignancies, were evaluated against non-metal-containing thiourea derivatives in earlier research.Low LC 50 values, spanning from 7 to 20 µM, were demonstrated by the findings [31].Furthermore, it has been discovered that thiourea derivatives target particular molecular pathways involved in the development of cancer, such as those that limit angiogenesis and alter cancer cell signaling pathways [32][33][34].With IC 50 values ranging from 3 to 14 µM, derivatives of phosphonate thiourea demonstrated encouraging responses when evaluated against cell lines related to pancreatic, prostate and breast cancer [35].The treatment of human leukemia cell lines with the bis-thiourea structure also demonstrated efficacy, with IC 50 values as low as 1.50 µM [36].Lung, liver and breast malignancies demonstrated positive LC 50 values of less than 20 µM for aromatic derivatives of thiourea produced using indole molecules [37].
Also, Samuel et al.
[38] conducted a thorough screening of several thiourea derivatives for toxicity in ovarian cancer cell lines, including those that showed cisplatin treatment resistance.Three molecules of luminescence iridium complexes based on a 2aminobenzimidazole unit were produced by the researchers.Through a substoichiometric 2-aminobenzimidazole reaction in acetonitrile, 1,1 ′ -thiocarbonyldiimidazole was monosubstituted efficiently.When compounds 32S-35S were purified, they had a 63-81% yield.This was due to a series of amines replacing the second imidazoyl unit in the presence of dimethylaminopyridine (DMAP) in dimethylformamide.Scheme 8 shows how iridium complexes based on these systems were subsequently created by reacting 33S with [Ir(ppy)2Cl]2 in toluene with potassium carbonate present.The result was bright yellow powders, or Ir-33S, in a 53% yield.

Anticancer Activity
In the fight against cancer, thiourea derivatives have demonstrated great promise.Studies conducted recently have demonstrated that these compounds can inhibit the growth of several cancer cell lines and reverse treatment resistance in cancer cells [25][26][27][28][29][30].A variety of human cell lines, including those from breast and lung malignancies, were evaluated against non-metal-containing thiourea derivatives in earlier research.Low LC50 values, spanning from 7 to 20 µM, were demonstrated by the findings [31].Furthermore, it has been discovered that thiourea derivatives target particular molecular pathways involved in the development of cancer, such as those that limit angiogenesis and alter cancer cell signaling pathways [32][33][34].With IC50 values ranging from 3 to 14 µM, derivatives of phosphonate thiourea demonstrated encouraging responses when evaluated against cell lines related to pancreatic, prostate and breast cancer [35].The treatment of human leukemia cell lines with the bis-thiourea structure also demonstrated efficacy, with IC50 values as low as 1.50 µM [36].Lung, liver and breast malignancies demonstrated positive LC50 values of less than 20 µM for aromatic derivatives of thiourea produced using indole molecules [37].
Also, Samuel et al.
[38] conducted a thorough screening of several thiourea derivatives for toxicity in ovarian cancer cell lines, including those that showed cisplatin treatment resistance.Three molecules of luminescence iridium complexes based on a 2-aminobenzimidazole unit were produced by the researchers.Through a substoichiometric 2aminobenzimidazole reaction in acetonitrile, 1,1′-thiocarbonyldiimidazole was monosubstituted efficiently.When compounds 32S-35S were purified, they had a 63−81% yield.This was due to a series of amines replacing the second imidazoyl unit in the presence of dimethylaminopyridine (DMAP) in dimethylformamide.Scheme 8 shows how iridium complexes based on these systems were subsequently created by reacting 33S with [Ir(ppy)2Cl]2 in toluene with potassium carbonate present.The result was bright yellow powders, or Ir-33S, in a 53% yield.Different human ovarian cancer cell lines, such as EFO-21, EFO-27 and COLO-704, as well as their cisplatin-resistant sublines, EFO-21rCDDP2000 and EFO-27rCDDP2000, were evaluated against a variety of unmetalled chemicals.With IC 50 values in the low micromolar range, these substances demonstrated toxicity in every cell line tested.Thioureas 32S, 33S and 35S were the most active compounds among those examined; their average IC 50 values were 1.29, 1.26 and 2.96 µM in all cell lines.In drug-resistant cell lines, the series 32S-35S exhibited a negligible decline in efficacy, but Ir-33S was found to be more effective in one resistant subline.
Targeting molecules different from cisplatin, gold complexes are another kind of chemical with anticancer effects.Gold compounds primarily target enzymes that include thiols, especially those that are located in mitochondria, like cyclooxygenases, glutathione reductase and thioredoxin reductase [39][40][41].The kind of ligand that is employed determines how stable gold complexes are in a biological setting.In the past 20 years, thiolate [42][43][44][45], phosphine [46][47][48][49][50][51] and N-heterocyclic carbene ligands, which are depicted in Figure 6, have all been widely employed and have demonstrated positive biological effects.
Different human ovarian cancer cell lines, such as EFO-21, EFO-27 and COLO-704, as well as their cisplatin-resistant sublines, EFO-21rCDDP2000 and EFO-27rCDDP2000 were evaluated against a variety of unmetalled chemicals.With IC50 values in the low micromolar range, these substances demonstrated toxicity in every cell line tested.Thioureas 32S, 33S and 35S were the most active compounds among those examined; their average IC50 values were 1.29, 1.26 and 2.96 µM in all cell lines.In drug-resistant cell lines, the series 32S-35S exhibited a negligible decline in efficacy, but Ir-33S was found to be more effective in one resistant subline.
Targeting molecules different from cisplatin, gold complexes are another kind of chemical with anticancer effects.Gold compounds primarily target enzymes that include thiols, especially those that are located in mitochondria, like cyclooxygenases, glutathione reductase and thioredoxin reductase [39][40][41].The kind of ligand that is employed determines how stable gold complexes are in a biological setting.In the past 20 years, thiolate [42][43][44][45], phosphine [46][47][48][49][50][51] and N-heterocyclic carbene ligands, which are depicted in Figure 6, have all been widely employed and have demonstrated positive biological effects.Because silver complexes are less toxic, they are useful in the therapy of cancer.Their principal mode of action is binding to proteins that contain thiols and DNA [53].Through a 1:1 reaction between the respective isothiocyanate a and b and 2-(diphenylphosphino) ethylamine (c), Guillermo et al. synthesized metal complex thioureas 36 and 37. Thioureas 36 (80% yield) and 37 (85% yield) were synthesized as shown in Scheme 9 [52].Scheme 9. Synthesis of thioureas 36 and 37 [52].
The synthesis of Ag(I) and Au(I) complexes from compounds 36 and 37 was carried out as shown in Schemes 10 and 11 [52].Because silver complexes are less toxic, they are useful in the therapy of cancer.Their principal mode of action is binding to proteins that contain thiols and DNA [53].Through a 1:1 reaction between the respective isothiocyanate a and b and 2-(diphenylphosphino) ethylamine (c), Guillermo et al. synthesized metal complex thioureas 36 and 37. Thioureas 36 (80% yield) and 37 (85% yield) were synthesized as shown in Scheme 9 [52].
IC50 values were 1.29, 1.26 and 2.96 µM in all cell lines.In drug-resistant cell lines, the series 32S-35S exhibited a negligible decline in efficacy, but Ir-33S was found to be more effective in one resistant subline.
Targeting molecules different from cisplatin, gold complexes are another kind of chemical with anticancer effects.Gold compounds primarily target enzymes that include thiols, especially those that are located in mitochondria, like cyclooxygenases, glutathione reductase and thioredoxin reductase [39][40][41].The kind of ligand that is employed determines how stable gold complexes are in a biological setting.In the past 20 years, thiolate [42][43][44][45], phosphine [46][47][48][49][50][51] and N-heterocyclic carbene ligands, which are depicted in Figure 6, have all been widely employed and have demonstrated positive biological effects.Because silver complexes are less toxic, they are useful in the therapy of cancer.Their principal mode of action is binding to proteins that contain thiols and DNA [53].Through a 1:1 reaction between the respective isothiocyanate a and b and 2-(diphenylphosphino) ethylamine (c), Guillermo et al. synthesized metal complex thioureas 36 and 37. Thioureas 36 (80% yield) and 37 (85% yield) were synthesized as shown in Scheme 9 [52].Scheme 9. Synthesis of thioureas 36 and 37 [52].
The synthesis of Ag(I) and Au(I) complexes from compounds 36 and 37 was carried out as shown in Schemes 10 and 11 [52].
The synthesis of Ag(I) and Au(I) complexes from compounds 36 and 37 was carried out as shown in Schemes 10 and 11 [52].
Three cancer cell lines, HeLa (human cervical carcinoma), A549 (human lung carcinoma) and Jurkat (leukaemia), were used to assess the toxicity of each synthesized complex.The toxicity test findings are shown in Tables 1 and 2.
Very low IC 50 values were discovered for the gold complexes in the complexes containing thiourea 36; however, all of the complexes with thiourea 37 showed improved cytotoxicity.
Three cancer cell lines, HeLa (human cervical carcinoma), A549 (human lung carcinoma) and Jurkat (leukaemia), were used to assess the toxicity of each synthesized complex.The toxicity test findings are shown in Tables 1 and 2. , 6, FOR PEER REVIEW 10 Scheme 10.Synthesis of metal complexes C36a-e derived from 36 [52].
Three cancer cell lines, HeLa (human cervical carcinoma), A549 (human lung carcinoma) and Jurkat (leukaemia), were used to assess the toxicity of each synthesized complex.The toxicity test findings are shown in Tables 1 and 2. Coordinators containing sulfur atoms frequently form metal complexes with thiourea derivatives, especially in complexes of transitional elements [54].A tetrahedron is the shape of copper, whereas the majority of these metal complexes are octahedral in shape [55,56].Five compounds of thiourea benzamide derivatives, shown in Scheme 12 [57], were synthesized by Yaqeen et al.These included ligands L1, L2, L3, L4 and L5 and their metal complexes, 38-42.Benzoyl chloride and ammonium thiocyanate were reacted to produce thiourea benzamide ligands, which were then used to synthesize the ligands.These ligands were subsequently used to create complex compounds 38-42 by reacting with Cu (II) ions in methanol and acetone.Using the MTT cytotoxicity assay against the MCF7 breast cancer cell lines, all of the produced compounds were evaluated.With IC 50 values of 4.03 and 4.66 µg/mL, respectively, complexes 38 and 39 were extremely effective, whereas the ligands had variable anti-cancer efficacy.Compounds 38 and 39 target the PR and Akt proteins of breast cancer cell lines (MCF-7), as demonstrated in Figure 7, based on the molecular docking of these compounds with target proteins 4OAR and 5KCV.Very low IC50 values were discovered for the gold complexes in the complexes containing thiourea 36; however, all of the complexes with thiourea 37 showed improved cytotoxicity.
Coordinators containing sulfur atoms frequently form metal complexes with thiourea derivatives, especially in complexes of transitional elements [54].A tetrahedron is the shape of copper, whereas the majority of these metal complexes are octahedral in shape [55,56].Five compounds of thiourea benzamide derivatives, shown in Scheme 12 [57], were synthesized by Yaqeen et al.These included ligands L1, L2, L3, L4 and L5 and their metal complexes, 38-42.Benzoyl chloride and ammonium thiocyanate were reacted to produce thiourea benzamide ligands, which were then used to synthesize the ligands.These ligands were subsequently used to create complex compounds 38-42 by reacting with Cu (II) ions in methanol and acetone.Using the MTT cytotoxicity assay against the MCF7 breast cancer cell lines, all of the produced compounds were evaluated.With IC50 values of 4.03 and 4.66 µg/mL, respectively, complexes 38 and 39 were extremely effective, whereas the ligands had variable anti-cancer efficacy.Compounds 38 and 39 target the PR and Akt proteins of breast cancer cell lines (MCF-7), as demonstrated in Figure 7, based on the molecular docking of these compounds with target proteins 4OAR and 5KCV.
The molecular docking analysis revealed that the three drugs exhibited groove binding, incomplete contact and mixed mode DNA binding.Furthermore, all three of the compounds (43-45) showed 2D interactions with the urease enzyme.N-N/diarylthiourea derivatives, which are included in a number of pharmaceutically active compounds, represent another interesting class of prospective anticancer medications [61][62][63].The molecular docking analysis revealed that the three drugs exhibited groove binding, incomplete contact and mixed mode DNA binding.Furthermore, all three of the compounds (43)(44)(45) showed 2D interactions with the urease enzyme.N-N/diarylthiourea derivatives, which are included in a number of pharmaceutically active compounds, represent another interesting class of prospective anticancer medications [61][62][63].
It is crucial to adjust the balance between the produced compounds' lipophilicity and hydrophilicity in order to look into the inhibitory mechanisms of the compounds.To enhance permeability through lipophilic cellular membranes, a lengthy non-polar alkyl ter-Scheme 13.Newly synthesized bis-thiourea derivatives: synthesis and structures [60].
It is crucial to adjust the balance between the produced compounds' lipophilicity and hydrophilicity in order to look into the inhibitory mechanisms of the compounds.To enhance permeability through lipophilic cellular membranes, a lengthy non-polar alkyl terminal chain containing six to sixteen carbon atoms must be included in the synthesis of novel diaryl thiourea derivatives.Moreover, adding a fluorine group as a hydrogen bond acceptor group can increase the proposed compounds' aqueous solubility [61].By combining phenolisocyanate or 4-fluorophenyl isothiocyanate with alkoxy anilines (4-hexyloxyaniline, 4-octyloxyaniline or 4-hexadecyloxyaniline) in dichloromethane at an ambient temperature, Mohamed et al. produced N, Nl disubstituted thiourea derivatives 46-51.Scheme 14 [64] shows the equimolar amounts used in this reaction that was conducted.
The molecular docking analysis revealed that the three drugs exhibited groove binding, incomplete contact and mixed mode DNA binding.Furthermore, all three of the compounds (43)(44)(45) showed 2D interactions with the urease enzyme.N-N/diarylthiourea derivatives, which are included in a number of pharmaceutically active compounds, represent another interesting class of prospective anticancer medications [61][62][63].
It is crucial to adjust the balance between the produced compounds' lipophilicity and hydrophilicity in order to look into the inhibitory mechanisms of the compounds.To enhance permeability through lipophilic cellular membranes, a lengthy non-polar alkyl terminal chain containing six to sixteen carbon atoms must be included in the synthesis of novel diaryl thiourea derivatives.Moreover, adding a fluorine group as a hydrogen bond acceptor group can increase the proposed compounds' aqueous solubility [61].By combining phenolisocyanate or 4-fluorophenyl isothiocyanate with alkoxy anilines (4-hexyloxyaniline, 4-octyloxyaniline or 4-hexadecyloxyaniline) in dichloromethane at an ambient temperature, Mohamed et al. produced N, Nl disubstituted thiourea derivatives 46-51.Scheme 14 [64] shows the equimolar amounts used in this reaction that was conducted.Scheme 14. Synthesis of urea and thiourea derivatives 46-51 [64].
The efficacy of the produced compounds in treating breast cancer was evaluated by testing them against MCF-7 cells.The findings indicated that compound 49 might have more promise as an anticancer drug due to its lower IC50 value (338.3 ± 1.52 µM).Unlike untreated control cells, treated MCF-7 cells with compound 49 displayed alterations in Scheme 14. Synthesis of urea and thiourea derivatives 46-51 [64].
The efficacy of the produced compounds in treating breast cancer was evaluated by testing them against MCF-7 cells.The findings indicated that compound 49 might have more promise as an anticancer drug due to its lower IC 50 value (338.3 ± 1.52 µM).Unlike untreated control cells, treated MCF-7 cells with compound 49 displayed alterations in cell size and shape as well as a progressive decline in cell viability, as the compound concentration increased, as seen in Figure 9.This outcome was comparable to that of 4-nitrobenzoyl-3-allylthiourea, another arylthiourea derivative that, at an IC 50 value of 225 µM, had good efficacy against breast cancer cells [65].
FOR PEER REVIEW 14 cell size and shape as well as a progressive decline in cell viability, as the compound concentration increased, as seen in Figure 9.This outcome was comparable to that of 4-nitrobenzoyl-3-allylthiourea, another arylthiourea derivative that, at an IC50 value of 225 µM, had good efficacy against breast cancer cells [65].Compound 49 was discovered to have a significant effect on LDH enzyme activity.The study indicated that treated MCF-7 cells had LDH levels that were 521.77 ± 30.8 U/L, significantly higher than those of untreated control cells (85.35 ± 4.2 U/L).According to these findings, compound 49 effectively prevents MCF-7 cell growth.In addition, the cell cycle of the treated cells was investigated.It was shown that a sizable portion of the cells were created in the S phase, suggesting that apoptosis was initiated and that the cell cycle Compound 49 was discovered to have a significant effect on LDH enzyme activity.The study indicated that treated MCF-7 cells had LDH levels that were 521.77 ± 30.8 U/L, significantly higher than those of untreated control cells (85.35 ± 4.2 U/L).According to these findings, compound 49 effectively prevents MCF-7 cell growth.In addition, the cell cycle of the treated cells was investigated.It was shown that a sizable portion of the cells were created in the S phase, suggesting that apoptosis was initiated and that the cell cycle was stopped at that point.This result demonstrates that compound 49 therapy is effective in stopping the growth of cancer cells and can disturb normal cell cycle progression [66,67].
The thiazole, pyrazole and pyran moieties found in several thiourea derivatives have also been shown to have promising anticancer action [68].Certain physicochemical and structural characteristics that impact thiourea's pharmacological properties are conferred by the integration of these heterocyclic moieties [69][70][71].Their therapeutic potential is increased by their interaction with molecular targets, which modify cellular activities and signaling cascades [72].Figure 10 [73] illustrates the series of thiourea derivatives that Ahmed et al. synthesized that contain heterocyclic moieties.4-Aminoacetophenone (i) was refluxed with phenyl isothiocyanate in dry toluene to form the pyrazole-based derivative 1-(4-acetylphenyl)-3-phenylthiourea (ii).This was then refluxed with the reagent, dimethylformamide-dimethyl acetal (DMF-DMA), in dioxane to convert it into its corresponding enaminone (iii).Compound iii reacted with two distinct nitrogen binucleophiles (phenyl hydrazine and hydrazine hydrate) via refluxing in ethanol and triethylamine, yielding compounds 50a and 50b, which are phenyl thiourea pyrazoles.Compound

Anti-Inflammatory Activity
Inflammation is characterized as a local or systemic reaction to injury to tissue or any other stimuli, including those that are chemical, physical, biological or thermal [75].

Anti-Inflammatory Activity
Inflammation is characterized as a local or systemic reaction to injury to tissue or any other stimuli, including those that are chemical, physical, biological or thermal [75].Hyperinflammation is brought on by an increase in the levels of proinflammatory markers, cytokines and inflammatory chemokines [76].Reactive oxygen species (ROS) and hyperinflammation work together to promote the growth of a number of illnesses, including diabetes, cancer, arthritis and cardiovascular disorders [77,78].Through a num-ber of cytokine-signaling pathways, two significant multifunctional pro-inflammatory cytokines-tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)-are involved in the pathophysiology of autoimmune, inflammatory, cardiovascular, neurological and cancer illnesses [79].Thus, TNF-α and IL-6 are crucial molecular targets for pharmaceuticals in the therapy of several illnesses [80].
Hyperinflammation is brought on by an increase in the levels of proinflammatory markers, cytokines and inflammatory chemokines [76].Reactive oxygen species (ROS) and hyperinflammation work together to promote the growth of a number of illnesses, including diabetes, cancer, arthritis and cardiovascular disorders [77,78].Through a number of cytokine-signaling pathways, two significant multifunctional pro-inflammatory cytokinestumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)-are involved in the pathophysiology of autoimmune, inflammatory, cardiovascular, neurological and cancer illnesses [79].Thus, TNF-α and IL-6 are crucial molecular targets for pharmaceuticals in the therapy of several illnesses [80].
Studies have demonstrated the good anti-inflammatory action of naproxen derivatives with substituted 1,2,4-triazole rings [83].Furthermore, it has been discovered in Two types of COX that are triggered by inflammatory stimuli are COX-1 and COX-2.5-LOX is an additional enzyme that contributes to lipid peroxidation and generates lipid peroxides.Inhibiting 5-LOX can aid in cognitive recovery, whereas increasing its activity is linked to neuroinflammation and may result in memory problems [82].The polyunsaturated omega-6 fatty acid arachidonic acid can be processed by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) via a variety of routes [82].
Studies have demonstrated the good anti-inflammatory action of naproxen derivatives with substituted 1,2,4-triazole rings [83].Furthermore, it has been discovered in multiple investigations that naproxen's thiourea derivatives have anti-inflammatory qualities.In comparison to naproxen, thiourea derivatives of naproxen in combination with aminopyridines [84], 4-chloroaniline [85] and amino acids [86] have exhibited negligible ulcerogenic effects and a greater percentage of paw edema reduction.
New thiourea derivatives of naproxen, including aromatic amines and aromatic amino acid esters, were produced by Nikola et al. [87].The synthesis process was followed as illustrated in Scheme 17.To create a modified naproxen scaffold, they started with S-naproxen.When aromatic amines were present, naproxenoyl chloride, which was created when naproxen and oxalyl chloride combined, could react with potassium thiocyanate to form compounds 67-71 or with esters of aromatic amino acids to form compounds 72 and 73.
Chemistry 2024, 6, FOR PEER REVIEW 18 multiple investigations that naproxen's thiourea derivatives have anti-inflammatory qualities.In comparison to naproxen, thiourea derivatives of naproxen in combination with aminopyridines [84], 4-chloroaniline [85] and amino acids [86] have exhibited negligible ulcerogenic effects and a greater percentage of paw edema reduction.New thiourea derivatives of naproxen, including aromatic amines and aromatic amino acid esters, were produced by Nikola et al. [87].The synthesis process was followed as illustrated in Scheme 17.To create a modified naproxen scaffold, they started with Snaproxen.When aromatic amines were present, naproxenoyl chloride, which was created when naproxen and oxalyl chloride combined, could react with potassium thiocyanate to form compounds 67-71 or with esters of aromatic amino acids to form compounds 72 and 73.Scheme 17. Synthesis of tested compounds [87].
The synthesized compounds were shown to be non-toxic and were evaluated for their anti-inflammatory properties using the acute inflammation model of carrageenan-induced paw edema, which is frequently employed in the testing of novel anti-inflammatory medications.It was discovered that a few of compounds 67-73 have the ability to suppress inflammation later on.Examining the effects of the produced molecule on COX-2 and 5-LOX, the findings revealed that none of the compounds inhibited COX-2 at concentrations below 100 µM by more than 50%, suggesting a poor inhibitory effect.As shown in Figure 11, compounds 67, 68, 69, 70 and 71, however, were capable of inhibiting 5-LOX, with compound 70 exhibiting the greatest efficiency.Its IC50 value (0.3 µM) was similar to those of commercial anti-inflammatory drugs [87,88].Scheme 17. Synthesis of tested compounds [87].
The synthesized compounds were shown to be non-toxic and were evaluated for their anti-inflammatory properties using the acute inflammation model of carrageenan-induced paw edema, which is frequently employed in the testing of novel anti-inflammatory medications.It was discovered that a few of compounds 67-73 have the ability to suppress inflammation later on.Examining the effects of the produced molecule on COX-2 and 5-LOX, the findings revealed that none of the compounds inhibited COX-2 at concentrations below 100 µM by more than 50%, suggesting a poor inhibitory effect.As shown in Figure 11, compounds 67, 68, 69, 70 and 71, however, were capable of inhibiting 5-LOX, with compound 70 exhibiting the greatest efficiency.Its IC 50 value (0.3 µM) was similar to those of commercial anti-inflammatory drugs [87,88].It has been discovered that urea-thiourea hybrids have a broad spectrum of antiinflammatory effects.Numerous new urea-thiourea hybrids have been created and thoroughly examined.These hybrids are created by reacting several isothiocyanate derivatives with 2,3-diaminonaphthalene-1,4-dione.These hybrids were shown to have anti-inflammatory properties on mammalian macrophages in an in vivo test by inhibiting PI3K activation and reducing the generation of proinflammatory cytokines [89].

Antituberculosis Activity
Due to the evolution of medication resistance, tuberculosis (TB), a lung disease caused by Mycobacterium tuberculosis (M.tuberculosis), continues to pose a serious threat to the world.As seen in Figure 12, the World Health Organization (WHO) estimates that 7.5 million individuals worldwide passed away from tuberculosis (TB) in 2022 [90].It has been discovered that urea-thiourea hybrids have a broad spectrum of antiinflammatory effects.Numerous new urea-thiourea hybrids have been created and thoroughly examined.These hybrids are created by reacting several isothiocyanate derivatives with 2,3-diaminonaphthalene-1,4-dione.These hybrids were shown to have antiinflammatory properties on mammalian macrophages in an in vivo test by inhibiting PI3K activation and reducing the generation of proinflammatory cytokines [89].

Antituberculosis Activity
Due to the evolution of medication resistance, tuberculosis (TB), a lung disease caused by Mycobacterium tuberculosis (M.tuberculosis), continues to pose a serious threat to the world.As seen in Figure 12, the World Health Organization (WHO) estimates that 7.5 million individuals worldwide passed away from tuberculosis (TB) in 2022 [90].A useful building block for the discovery of novel pharmaceuticals with a variety of therapeutic uses is the thiourea scaffold.An essential component of M. tuberculosis's mycolic acid production pathway is InhA, an enoyl-acyl carrier protein reductase.Because of this, InhA is essential for the growth of M. tuberculosis (TB) and presents a promising target for the development of novel antituberculosis drugs [91].Şengül et al. [92] synthesized thiourea derivatives 74 and 75, depicted in Figure 13, which possess essential structural components to function as InhA inhibitors and growth inhibitors of M. tuberculosis.Five thiourea derivatives were synthesized by Emine et al. [93] and are represented in Figure 14   A useful building block for the discovery of novel pharmaceuticals with a variety of therapeutic uses is the thiourea scaffold.An essential component of M. tuberculosis's mycolic acid production pathway is InhA, an enoyl-acyl carrier protein reductase.Because of this, InhA is essential for the growth of M. tuberculosis (TB) and presents a promising target for the development of novel antituberculosis drugs [91].Şengül et al. [92] synthesized thiourea derivatives 74 and 75, depicted in Figure 13, which possess essential structural components to function as InhA inhibitors and growth inhibitors of M. tuberculosis.A useful building block for the discovery of novel pharmaceuticals with a variety of therapeutic uses is the thiourea scaffold.An essential component of M. tuberculosis's mycolic acid production pathway is InhA, an enoyl-acyl carrier protein reductase.Because of this, InhA is essential for the growth of M. tuberculosis (TB) and presents a promising target for the development of novel antituberculosis drugs [91].Şengül et al. [92] synthesized thiourea derivatives 74 and 75, depicted in Figure 13, which possess essential structural components to function as InhA inhibitors and growth inhibitors of M. tuberculosis.Five thiourea derivatives were synthesized by Emine et al. [93] and are represented in Figure 14   Five thiourea derivatives were synthesized by Emine et al. [93] and are represented in Figure 14   Anna et al. [94], investigated the antitubercular capabilities of a series of halogenated copper (II) complexes.To assess the impact of substitution isomerism and electron-withdrawing functions, they employed various phenyl ring substituent arrangements.Among the thiourea derivative complexes were those containing 1-( 2  Anna et al. [94], investigated the antitubercular capabilities of a series of halogenated copper (II) complexes.To assess the impact of substitution isomerism and electronwithdrawing functions, they employed various phenyl ring substituent arrangements.Among the thiourea derivative complexes were those containing 1-  The synthesis and assessment of urea and thiourea derivatives of 5-phenyl-3isoxazolecarboxylic acid methyl esters, which exhibit promise as anti-TB drugs, were reported by Santosh et al. [95].Developing medications that work requires a deep comprehension of the Structure-Activity Relationship (SAR), as shown in Figure 16.This led to the synthesis of a number of thiourea derivatives based on isoxazole carboxylic acid methyl ester, as shown in Figure 17.The synthesis and assessment of urea and thiourea derivatives of 5-phenyl-3-isoxazolecarboxylic acid methyl esters, which exhibit promise as anti-TB drugs, were reported by Santosh et al. [95].Developing medications that work requires a deep comprehension of the Structure-Activity Relationship (SAR), as shown in Figure 16.This led to the synthesis of a number of thiourea derivatives based on isoxazole carboxylic acid methyl ester, as shown in Figure 17.When synthetic compounds 89-102 were examined for their ability to combat tuberculosis (TB), they all displayed nearly identical levels of efficacy.The most potent monosubstituted thiourea derivatives were those containing a chlorine atom, with p-chloro being the most active (MIC 1 µg/mL).On the other hand, the m-chloro and m-bromo compounds only showed a moderate level of efficacy.The 2,4-difluoro derivatives among the disubstituted analogs exhibited good efficacy (MIC 2 µg/mL).culosis (TB), they all displayed nearly identical levels of efficacy.The most potent monosubstituted thiourea derivatives were those containing a chlorine atom, with p-chloro being the most active (MIC 1 µg/mL).On the other hand, the m-chloro and m-bromo compounds only showed a moderate level of efficacy.The 2,4-difluoro derivatives among the disubstituted analogs exhibited good efficacy (MIC 2 µg/mL).When synthetic compounds 89-102 were examined for their ability to combat tuberculosis (TB), they all displayed nearly identical levels of efficacy.The most potent monosubstituted thiourea derivatives were those containing a chlorine atom, with p-chloro being the most active (MIC 1 µg/mL).On the other hand, the m-chloro and m-bromo compounds only showed a moderate level of efficacy.The 2,4-difluoro derivatives among the disubstituted analogs exhibited good efficacy (MIC 2 µg/mL).

Anti-Alzheimer
Dementia may result from Alzheimer's disease, a degenerative and crippling neurological condition that impairs cognitive function.Studies indicate that hereditary variables, including apolipoprotein E, can contribute to the onset of the illness.The two main processes that harm neural cells are oxidative damage and inflammation [96][97][98].Research has demonstrated the potential application of sulfur-containing compounds, including thiols, disulfides and sulfides, in the treatment of Alzheimer's disease (Figure 18).In addition, various classes of compounds containing sulfur have demonstrated promise in the treatment of the disease, such as sulfoxides and thiocarboxylic acids with a +4 oxidation state, thioesters, thioketones, thioureas and heterocyclic compounds containing sulfur with a −2 oxidation state, and sulfones and sulfonamides with a +6 oxidation state [99,100].
Targeting the enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), which are essential for the breakdown of different compounds, is the goal of treating Alzheimer's disease (AD).BChE also aids in the breakdown of ACh in a healthy brain, exacerbating the course of AD.In order to cure AD, it may be beneficial to inhibit both AChE and BChE [101].As illustrated in Figure 19, AChE inhibitors such as donepezil, rivastigmine and galantamine are currently the most often prescribed medications for AD in clinics.Patients with mild to moderate AD may obtain symptom relief from these inhibitors, which interfere with the enzyme's active site [102].
thiols, disulfides and sulfides, in the treatment of Alzheimer's disease (Figure 18).In addition, various classes of compounds containing sulfur have demonstrated promise in the treatment of the disease, such as sulfoxides and thiocarboxylic acids with a +4 oxidation state, thioesters, thioketones, thioureas and heterocyclic compounds containing sulfur with a -2 oxidation state, and sulfones and sulfonamides with a +6 oxidation state [99,100].Targeting the enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), which are essential for the breakdown of different compounds, is the goal of treating Alzheimer's disease (AD).BChE also aids in the breakdown of ACh in a healthy brain, exacerbating the course of AD.In order to cure AD, it may be beneficial to inhibit both AChE and BChE [101].As illustrated in Figure 19, AChE inhibitors such as donepezil, rivastigmine and galantamine are currently the most often prescribed medications for AD in clinics.Patients with mild to moderate AD may obtain symptom relief from these inhibitors, which interfere with the enzyme's active site [102].As shown in Figure 20, Mehtab et al. [103] produced a range of thiourea and thiazolidinone compounds, 103-106, and investigated their inhibitory activity against AChE and BChE.
The compounds showed varying degrees of inhibitory efficacy against AChE and BChE, according to the study.In particular, 103 < 105 < 104 was the sequence of inhibitory activities against AChE, whereas 105 < 104 < 103 < 106 was the sequence against BChE.The compound's IC 50 values against AChE and BChE were 33.27-93.85nM and 105.9-412.5 nM, respectively.All results showed that the compounds worked better against AChE than they did against BChE [103].There have also been reports of other thiourea compounds acting as enzyme inhibitors, including isobutylphenylthiourea and tert-butylphenylthiourea [104].Six crystalline thiourea derivatives were evaluated against BChE and AChE in a different investigation [105].Figure 21 displays the compounds that were produced.The compounds showed varying degrees of inhibitory efficacy against AChE and BChE, according to the study.In particular, 103 < 105 < 104 was the sequence of inhibitory activities against AChE, whereas 105 < 104 < 103 < 106 was the sequence against BChE.The compound's IC50 values against AChE and BChE were 33.27-93.85nM and 105.9-412.5 nM, respectively.All results showed that the compounds worked better against AChE than they did against BChE [103].There have also been reports of other thiourea compounds acting as enzyme inhibitors, including isobutylphenylthiourea and tert-butylphenylthiourea [104].Six crystalline thiourea derivatives were evaluated against BChE and AChE in a different investigation [105].Figure 21 displays the compounds that were produced.

Antimalarial Activity
The parasite Plasmodium, a member of the phylum Apicomplexa, is the cause of malaria.About 50% of people worldwide are at risk of malaria, according to the World Health Organization (WHO) [107].Malaria poses a threat to about half of the world's population.Drug-resistant forms of the malaria parasite have emerged as a result of the indiscriminate use of antimalarial medications like artemisinin and chloroquine.To tackle antimalarial drug resistance, Cheo et al. [108] and Mohamed et al. [109] synthesized promising compounds with chalcone pyrazoline and pyrimidine scaffolds, as seen in Figure 23.

Antimalarial Activity
The parasite Plasmodium, a member of the phylum Apicomplexa, is the cause of malaria.About 50% of people worldwide are at risk of malaria, according to the World Health Organization (WHO) [107].Malaria poses a threat to about half of the world's population.Drug-resistant forms of the malaria parasite have emerged as a result of the indiscriminate use of antimalarial medications like artemisinin and chloroquine.To tackle antimalarial drug resistance, Cheo et al. [108] and Mohamed et al. [109] synthesized promising compounds with chalcone pyrazoline and pyrimidine scaffolds, as seen in Figure 23.All of the produced compounds were evaluated to see how well they worked against the chloroquine-resistant RKL9 strain of malaria, as well as the chloroquine-sensitive 3D7 strain.Next, the compounds' IC50 values were contrasted with those of chloroquine.Chalcones 113-116 were shown to be less efficient than the heterocyclic compound produced from them in combating P. falciparum malaria.Furthermore, it was shown that molecules Scheme 20.Synthesis of pyrimidine derivatives 113-116B(i-iii) [109].
All of the produced compounds were evaluated to see how well they worked against the chloroquine-resistant RKL9 strain of malaria, as well as the chloroquine-sensitive 3D7 strain.Next, the compounds' IC 50 values were contrasted with those of chloroquine.Chalcones 113-116 were shown to be less efficient than the heterocyclic compound produced from them in combating P. falciparum malaria.Furthermore, it was shown that molecules with a methoxy group in the para position were more potent than those with a methoxy group in the meta position.An investigation into molecular docking was carried out on the ATPase 'PfATP4' enzyme, which is thought to be essential for resistance mechanisms.The strongest binding energies to the "PfATP4" receptor were exhibited by compounds 113, 113Aiii and 113Bi, out of all the produced derivatives, according to the results.Figure 24 shows the compound model with the effective functional groups.
hemistry 2024, 6, FOR PEER REVIEW 28 with a methoxy group in the para position were more potent than those with a methoxy group in the meta position.An investigation into molecular docking was carried out on the ATPase 'PfATP4' enzyme, which is thought to be essential for resistance mechanisms.
The strongest binding energies to the "PfATP4" receptor were exhibited by compounds 113, 113Aiii and 113Bi, out of all the produced derivatives, according to the results.Figure 24 shows the compound model with the effective functional groups.

The Recent Strategies in the Synthesis of Thiourea Derivatives
As a result of the environmental problems associated with the diversity of the traditional chemical synthesis of organic compounds, the trend of using green chemistry was the alternative to avoid these problems.The automated synthetic systems were a useful tool to accelerate the research of organic synthesis and reduce the harm of chemicals to

The Recent Strategies in the Synthesis of Thiourea Derivatives
As a result of the environmental problems associated with the diversity of the traditional chemical synthesis of organic compounds, the trend of using green chemistry was the alternative to avoid these problems.The automated synthetic systems were a useful tool to accelerate the research of organic synthesis and reduce the harm of chemicals to the human body [110,111].
Capsaicin derivatives with thiourea structures (CDTS) are known for their higher analgesic potency in rodent models and higher agonism in vitro.As shown in Figure 25, capsaicin derivatives with thiourea structures showed higher analgesic potency in rodent models and higher agonism in vitro [112].Lina et al. [113] reported a green, facile and practical synthetic method for capsaicin derivatives with thiourea structures, which was developed by using an automated synthetic system, as shown in Figure 26.The synthesis of CDTS was performed via a condensation reaction of vanilylamine hydrochloride and isothiocyanates at room temperature and under green solvent (water) conditions with goo/excellent yields [113].

Conclusions
Thiourea is a significant compound that is used as a basic building block to synthesize a wide range of derivatives with different biological activities.Strong antibacterial and anticancer effects have been demonstrated by these derivatives, which also comprise tris thioureas, complexes and symmetrical and asymmetrical bis thioureas.In addition, urea-thiourea hybrids have shown notable anti-inflammatory properties, and other thio-

Conclusions
Thiourea is a significant compound that is used as a basic building block to synthesize a wide range of derivatives with different biological activities.Strong antibacterial and anticancer effects have been demonstrated by these derivatives, which also comprise tris thioureas, complexes and symmetrical and asymmetrical bis thioureas.In addition,

Conclusions
Thiourea is a significant compound that is used as a basic building block to synthesize a wide range of derivatives with different biological activities.Strong antibacterial and anticancer effects have been demonstrated by these derivatives, which also comprise tris thioureas, complexes and symmetrical and asymmetrical bis thioureas.In addition, urea-thiourea hybrids have shown notable anti-inflammatory properties, and other thiourea-containing pyrazole, thiazole and pyran moieties have shown a variety of biological activities.Herien, I highlight several therapeutic applications and the development of synthetic strategies.I track the progress in this field by discussing traditional methods, green chemistry and, recently, the automated synthetic system.This system can be considered the starting point for improving not only the quality but also the quantity of the targeted product, while maintaining a healthy environment.According to the abovementioned information, I hope that this review will motivate researchers to conduct more research in this exciting field.
Funding: This research received no external funding.

Figure 2 .
Figure 2. Equilibrium between the tautomeric forms of thiourea.Figure 2. Equilibrium between the tautomeric forms of thiourea.

Figure 3 .
Figure 3. Different forms of biologically active thiourea derivatives.

Figure 3 .
Figure 3. Different forms of biologically active thiourea derivatives.

Figure 9 .
Figure 9. Comparing the morphological changes in MCF-7 cells treated for 24 h with different doses (50-1000 µM) of compound 49 to untreated control cells under a microscope [64].

Figure 9 .
Figure 9. Comparing the morphological changes in MCF-7 cells treated for 24 h with different doses (50-1000 µM) of compound 49 to untreated control cells under a microscope [64].

Figure 16 .
Figure 16.Overview of SAR of evaluated compounds.Highlighted colors of rectangular boxes indicate the identical color of part of the structure [95].

Figure 16 .
Figure 16.Overview of SAR of evaluated compounds.Highlighted colors of rectangular boxes indicate the identical color of part of the structure [95].

Figure 22 .
Figure 22.Three-dimensional binding interaction modes of compounds 109 and 110 as inhibitors of AChE and BChE.(a,b) Interaction posing of compound 109 and 110 with AChE, respectively; (c,d) Interaction of compound 109 and 110 with BChE, respectively [105].

Figure 22 .
Figure 22.Three-dimensional binding interaction modes of compounds 109 and 110 as inhibitors of AChE and BChE.(a,b) Interaction posing of compound 109 and 110 with AChE, respectively; (c,d) Interaction of compound 109 and 110 with BChE, respectively [105].In comparison with the normal donepezil (IC 50 , 2.16 and 4.5 µM, respectively), thiazolethiourea hybrid compounds have recently demonstrated exceptional activity against both AChE and BChE enzymes, with IC 50 values ranging from 0.3 to 15 µM against AChE and 0.4 to 22 µM against BChE [106].

Chemistry 2024, 6 , 29 Figure 25 .
Figure 25.Capsaicin derivatives with thiourea structures[113].The blue content is the structure of the nucleus of capsaicin and the red parts are the substituted parts either without(upper) or with thiourea (lower).

Figure 25 .
Figure 25.Capsaicin derivatives with thiourea structures[113].The blue content is the structure of the nucleus of capsaicin and the red parts are the substituted parts either without (upper) or with thiourea (lower).

Chemistry 2024, 6 , 29 Figure 25 .
Figure 25.Capsaicin derivatives with thiourea structures[113].The blue content is the structure of the nucleus of capsaicin and the red parts are the substituted parts either without(upper) or with thiourea (lower).

Table 1 .
[52]tumor activity expressed in IC50 values of complexes C36a-e compared with that of thiourea 36 as the standard[52].

Table 1 .
[52]tumor activity expressed in IC50 values of complexes C36a-e compared with that of thiourea 36 as the standard[52].

Table 1 .
[52]tumor activity expressed in IC 50 values of complexes C36a-e compared with that of thiourea 36 as the standard[52].
a Each value represents the mean ± standard deviation from three independent experiments.b Cisplatin dissolved in DMSO.c Cisplatin dissolved in H 2 O.

Table 2 .
[52]tumor activity expressed in IC 50 values of complexes C36a-e compared with that of thiourea 37 as the standard[52].

Table 2 .
[52]tumor activity expressed in IC50 values of complexes C36a-e compared with that of thiourea 37 as the standard[52].
a Each value represents the mean ± standard deviation from three independent experiments.