Synthetic Transformations and Medicinal Significance of 1,2,3-Thiadiazoles Derivatives: An Update

The 1,2,3-thiadiazole moiety occupies a significant and prominent position among privileged heterocyclic templates in the field of medicine, pharmacology and pharmaceutics due to its broad spectrum of biological activities. The 1,2,3-thiadiazole hybrid structures showed myriad biomedical activities such as antifungal, antiviral, insecticidal, antiamoebic, anticancer and plant activators, etc. In the present review, various synthetic transformations and approaches are highlighted to furnish 1,2,3-thiadiazole scaffolds along with different pharmaceutical and pharmacological activities by virtue of the presence of the 1,2,3-thiadiazole framework on the basis of structure–activity relationship (SAR). The discussion in this review article will attract the attention of synthetic and medicinal researchers to explore 1,2,3-thiadiazole structural motifs for future therapeutic agents.


Introduction
The fascinating aromatic 1,2,3-thiadiazole is a structurally active pharmacophore and great interest for researchers due to its versatile and wide array of biological activities in the field of medicine, pharmacology and pharmaceutics. Thiadiazoles occur naturally in four different isomeric forms, having one sulfur and two nitrogen atoms with hydrogen binding domain as presented in Figure 1 [1][2][3][4].

Hurd-Mori and Lalezari Cyclization
Pyrazolyl-1,2,3-thiadiazole scaffolds were afforded through carbon-sulfur, carbon double bonded with nitrogen and nitrogen-sulfur bonds formation by applying Hurd-Mori cyclization conditions as described in Scheme 1. In this efficient synthetic approach, various pyrazolyl-phenylethanones (15) were reacted with semicarbazide (16) to generate corresponding semicarbazone (17) intermediate that cyclized into substituted The bioactive 1,2,3-thiadiazole analogues display excellent and outstanding new profiles of medicinal, pharmacological and pharmaceutical activities [1,77]. In this review article, the most recent and relevant synthetic approaches and pharmacological activities of 1,2,3-thiadiazole analogues are discussed and can be classified into antiviral, insecticidal, antifungal and anticancer activities.

Ultrasonic Assisted Synthesis of 1,2,3-Thiadiazoles
An interesting example of the use of the ultrasonic-assisted technique is the synthesis described by Dong et al. (Scheme 10). In this multi-step synthetic route, the 5-carboxylic acid substituted thiadiazole (54) was reacted with thionyl chloride to obtain its corresponding 5-carbonyl chloride derivative (55), which in the next step was combined with glycine to afford carboxamide derivative (56). The last one (56) was reacted with substituted benzaldehyde and Ac2O under the ultrasonic-assisted irradiations conditions to furnish 4-benzylideneoxazole moiety containing 4-methyl-1,2,3-thiadiazole (57). In further steps, the oxazole derivative (57) was subjected to reaction with piperidine to obtain the intermediate (58) which further halogenated in chloroform to afford final substituted phenyl acrylamide 1,2,3-thiadiazole derivatives (59) in 73.9-99% yield [86].

Ultrasonic Assisted Synthesis of 1,2,3-Thiadiazoles
An interesting example of the use of the ultrasonic-assisted technique is the synthesis described by Dong et al. (Scheme 10). In this multi-step synthetic route, the 5-carboxylic acid substituted thiadiazole (54) was reacted with thionyl chloride to obtain its corresponding 5-carbonyl chloride derivative (55), which in the next step was combined with glycine to afford carboxamide derivative (56). The last one (56) was reacted with substituted benzaldehyde and Ac 2 O under the ultrasonic-assisted irradiations conditions to furnish 4-benzylideneoxazole moiety containing 4-methyl-1,2,3-thiadiazole (57). In further steps, the oxazole derivative (57) was subjected to reaction with piperidine to obtain the intermediate (58) which further halogenated in chloroform to afford final substituted phenyl acrylamide 1,2,3-thiadiazole derivatives (59) in 73.9-99% yield [86].

Hydrolization and Esterification Approach
Scheme 11. Acetohydrazone as starting precursor for the preparation of thiadiazoles (64).

[4+1]. Annulation of Azoalkenes
A new sustainable, regioselective, environmentally friendly and broad functional-group compatibility synthetic strategy for thiadiazoles was described by Zhang et al. In their protocol, photocatalysis reaction of azoalkenes (76) with KSCN in the presence of cercosporin and t BuOK afforded desired thiadiazoles (77). Electron donating groups showed maximum yield, week EWD groups displayed good yield. Strong EWD groups Scheme 12. Synthesis of new carboxylate derivatives of thiadiazoles (67).

[4+1]. Annulation of Azoalkenes
A new sustainable, regioselective, environmentally friendly and broad functional-group compatibility synthetic strategy for thiadiazoles was described by Zhang et al. In their protocol, photocatalysis reaction of azoalkenes (76) with KSCN in the presence of cercosporin and t BuOK afforded desired thiadiazoles (77). Electron donating groups showed maximum yield, week EWD groups displayed good yield. Strong EWD groups Scheme 13. Synthesis of substituted 1,2,3-thiadiazole (71) via cross-coupling mediated by I 2 /DMSO.

[4+1]. Annulation of Azoalkenes
A new sustainable, regioselective, environmentally friendly and broad functional-group compatibility synthetic strategy for thiadiazoles was described by Zhang et al. In their protocol, photocatalysis reaction of azoalkenes (76) with KSCN in the presence of cercosporin and t BuOK afforded desired thiadiazoles (77). Electron donating groups showed maximum yield, week EWD groups displayed good yield. Strong EWD groups Scheme 14. Synthesis of 1,2,3-thiadiazoles (75) via nucleophilic addition.

[4 + 1]. Annulation of Azoalkenes
A new sustainable, regioselective, environmentally friendly and broad functionalgroup compatibility synthetic strategy for thiadiazoles was described by Zhang et al. In their protocol, photocatalysis reaction of azoalkenes (76) with KSCN in the presence of cercosporin and t BuOK afforded desired thiadiazoles (77). Electron donating groups showed maximum yield, week EWD groups displayed good yield. Strong EWD groups afforded moderate yield, heterocyclic moiety such as furan showed the least yield while pyridine did not furnish yield under the conditions as mentioned in Scheme 15 [91]. afforded moderate yield, heterocyclic moiety such as furan showed the least yield while pyridine did not furnish yield under the conditions as mentioned in Scheme 15 [91].
Appl. Sci. 2021, 11, x FOR PEER REVIEW 9 of 30 afforded moderate yield, heterocyclic moiety such as furan showed the least yield while pyridine did not furnish yield under the conditions as mentioned in Scheme 15 [91].
Appl. Sci. 2021, 11, x FOR PEER REVIEW 9 of afforded moderate yield, heterocyclic moiety such as furan showed the least yield whi pyridine did not furnish yield under the conditions as mentioned in Scheme 15 [91].

Biological Activities of 1,2,3-Thiadiazole Derivatives
The main objective of the present section is the search and presentation of the 1,2,3-thiadiazole based most potent therapeutic agents for a variety of biological and pharmacological applications with little or no side effects. In this section, 1,2,3-thiadiazole derivatives have been divided into classes according to their biological activity.

Antiviral Agents
Pawar et al. described antiviral drugs as such bioactive compounds which are used for the treatment of viral infections [96]. Rossignol et al. reported that most of the antiviral agents are specifically targeted oriented while some other antivirals have a broad spectrum against a vast variety of viral infections [97]. Some antiviral drugs such as ribavirin (89; Figure 3) are being used against both RNA and DNA viruses [98][99][100], efavirenz (90; Figure 3) used for the treatment of HIV/AIDS [101][102][103] and arbidol (91; Figure  3) was used against influenza viruses [104,105].

Biological Activities of 1,2,3-Thiadiazole Derivatives
The main objective of the present section is the search and presentation of the 1,2,3-thiadiazole based most potent therapeutic agents for a variety of biological and pharmacological applications with little or no side effects. In this section, 1,2,3-thiadiazole derivatives have been divided into classes according to their biological activity.

Antiviral Agents
Pawar et al. described antiviral drugs as such bioactive compounds which are used for the treatment of viral infections [96]. Rossignol et al. reported that most of the antiviral agents are specifically targeted oriented while some other antivirals have a broad spectrum against a vast variety of viral infections [97]. Some antiviral drugs such as ribavirin (89; Figure 3) are being used against both RNA and DNA viruses [98][99][100], efavirenz (90; Figure 3) used for the treatment of HIV/AIDS [101][102][103] and arbidol (91; Figure  3) was used against influenza viruses [104,105]. Scheme 19. Synthesis of 1,2,3-thiadiazoles from in situ generated azoalkenes with S 3 •− via a cascade process.

Biological Activities of 1,2,3-Thiadiazole Derivatives
The main objective of the present section is the search and presentation of the 1,2,3thiadiazole based most potent therapeutic agents for a variety of biological and pharmacological applications with little or no side effects. In this section, 1,2,3-thiadiazole derivatives have been divided into classes according to their biological activity.

Antiviral Agents
Pawar et al. described antiviral drugs as such bioactive compounds which are used for the treatment of viral infections [96]. Rossignol et al. reported that most of the antiviral agents are specifically targeted oriented while some other antivirals have a broad spectrum against a vast variety of viral infections [97]. Some antiviral drugs such as ribavirin (89; Figure 3) are being used against both RNA and DNA viruses [98][99][100], efavirenz (90; Figure 3) used for the treatment of HIV/AIDS [101][102][103] and arbidol (91; Figure 3) was used against influenza viruses [104,105].  Zhan et al. prepared 1,2,3-thiadiazole thioacetanilide by adopting a multi-step methodology and exhibited their anti-HIV (Human Immunodeficiency Virus) activity against MT-4 cells. Among all synthesized derivatives, the thioacetanilide based 1,2,3-thiadiazole scaffold (92; Figure 4) showed remarkably the best anti-HIV activity in terms of EC50 value 0.059 ± 0.02 µM, CC50 > 283.25 µM, SI > 4883 µM compared to the reference compounds such as NVP (nevirapine) DLV (delaviridine), EFV (Efavirenz), AZT (azidothymidine) and VRX-480773. SAR displayed that the significant enhancement in the antiviral efficacy of compound 92 was due to the introduction of the nitro group on the phenyl ring. Anilide scaffold having NO2 and halogen-substituted aryl ring at o-position took great part to enhance the anti-HIV potential, however, the case was the difference for fluorine atom which decreased activity at a certain level [106].  Zhan et al. prepared 1,2,3-thiadiazole thioacetanilide by adopting a multi-step methodology and exhibited their anti-HIV (Human Immunodeficiency Virus) activity against MT-4 cells. Among all synthesized derivatives, the thioacetanilide based 1,2,3-thiadiazole scaffold (92; Figure 4) showed remarkably the best anti-HIV activity in terms of EC 50 value 0.059 ± 0.02 µM, CC 50 > 283.25 µM, SI > 4883 µM compared to the reference compounds such as NVP (nevirapine) DLV (delaviridine), EFV (Efavirenz), AZT (azidothymidine) and VRX-480773. SAR displayed that the significant enhancement in the antiviral efficacy of compound 92 was due to the introduction of the nitro group on the phenyl ring. Anilide scaffold having NO 2 and halogen-substituted aryl ring at o-position took great part to enhance the anti-HIV potential, however, the case was the difference for fluorine atom which decreased activity at a certain level [106].  Figure 4) showed remarkably the best anti-HIV activity in terms of EC50 value 0.059 ± 0.02 µM, CC50 > 283.25 µM, SI > 4883 µM compared to the reference compounds such as NVP (nevirapine) DLV (delaviridine), EFV (Efavirenz), AZT (azidothymidine) and VRX-480773. SAR displayed that the significant enhancement in the antiviral efficacy of compound 92 was due to the introduction of the nitro group on the phenyl ring. Anilide scaffold having NO2 and halogen-substituted aryl ring at o-position took great part to enhance the anti-HIV potential, however, the case was the difference for fluorine atom which decreased activity at a certain level [106].  Dong et al. prepared potent antiviral piperidine-based thiadiazole derivatives, and the SAR study showed that chlorine atom substituted compounds exhibited good antiviral activity and the substitution on phenyl ring affects inhibitory action. 1,2,3-thiadiazole (94; Figure 6) displayed excellent potency with IC 50 3.59 µg/mL as compared to lamivudine (IC 50 value 14.8 µg/mL). It was observed that compounds having p-substituents exhibited more cytotoxic potency than the o-substituted derivatives. Moreover, lowering of the selective index with higher anti-HBV potencies of the synthesized compounds was observed when comparing the results with lamivudine. Compound 94 proved to be the most active one as compared to the other derivatives [86]. Dong et al. prepared potent antiviral piperidine-based thiadiazole derivatives, and the SAR study showed that chlorine atom substituted compounds exhibited good antiviral activity and the substitution on phenyl ring affects inhibitory action. 1,2,3-thiadiazole (94; Figure 6) displayed excellent potency with IC50 3.59 µg/mL as compared to lamivudine (IC50 value 14.8 µg/mL). It was observed that compounds having p-substituents exhibited more cytotoxic potency than the o-substituted derivatives. Moreover, lowering of the selective index with higher anti-HBV potencies of the synthesized compounds was observed when comparing the results with lamivudine. Compound 94 proved to be the most active one as compared to the other derivatives [86]. Synthesis and screening of antiviral potency of tetrazole-based 1,2,3-thiadiazoles structural against tobacco mosaic virus (TMV, anti-TMV) were evaluated [84]. The studies indicated that some obtained compounds (95-98; Figure 7) have higher anti-TMV activity (33.75-48.73%) than ribavirin at 100mg/mL concentration (33.23%) and comparable potency to ribavirin at 100 µg/mL. Structure 97 displayed the best protection effect among the synthesized derivatives as well as from the ribavirin-reference drug. Anti-TMV activity of synthesized scaffolds and reference drugs decreases in order of 98 > ninamycin >97 > 95 > 96 > ribavirin while the protection effect decreased in order of ninamycin > 97 > 96 > 95> ribavirin > 98. Compound 98 display a higher inhibition potential, i.e., 48.73% as compared to ninamycin and ribavirin. The SAR study showed that the 2-fluorophenyl substituent derivative 97displayed the best protection effect among the synthesized congeners as well as from the ribavirin reference drug. The protection effect decreased in order of ninamycin > 2-fluorophenyl > cyclopropyl > isopropyl > ribavirin > 4-ethylphenyl. Overall the scaffold 97 proved to be a promising therapeutic agent, which has a better protection effect as well as the best anti-TMV activity [84]. Dong et al. prepared potent antiviral piperidine-based thiadiazole derivatives, and the SAR study showed that chlorine atom substituted compounds exhibited good antiviral activity and the substitution on phenyl ring affects inhibitory action. 1,2,3-thiadiazole (94; Figure 6) displayed excellent potency with IC50 3.59 µg/mL as compared to lamivudine (IC50 value 14.8 µg/mL). It was observed that compounds having p-substituents exhibited more cytotoxic potency than the o-substituted derivatives. Moreover, lowering of the selective index with higher anti-HBV potencies of the synthesized compounds was observed when comparing the results with lamivudine. Compound 94 proved to be the most active one as compared to the other derivatives [86]. Synthesis and screening of antiviral potency of tetrazole-based 1,2,3-thiadiazoles structural against tobacco mosaic virus (TMV, anti-TMV) were evaluated [84]. The studies indicated that some obtained compounds (95-98; Figure 7) have higher anti-TMV activity (33.75-48.73%) than ribavirin at 100mg/mL concentration (33.23%) and comparable potency to ribavirin at 100 µg/mL. Structure 97 displayed the best protection effect among the synthesized derivatives as well as from the ribavirin-reference drug. Anti-TMV activity of synthesized scaffolds and reference drugs decreases in order of 98 > ninamycin >97 > 95 > 96 > ribavirin while the protection effect decreased in order of ninamycin > 97 > 96 > 95> ribavirin > 98. Compound 98 display a higher inhibition potential, i.e., 48.73% as compared to ninamycin and ribavirin. The SAR study showed that the 2-fluorophenyl substituent derivative 97displayed the best protection effect among the synthesized congeners as well as from the ribavirin reference drug. The protection effect decreased in order of ninamycin > 2-fluorophenyl > cyclopropyl > isopropyl > ribavirin > 4-ethylphenyl. Overall the scaffold 97 proved to be a promising therapeutic agent, which has a better protection effect as well as the best anti-TMV activity [84]. Synthesis and screening of antiviral potency of tetrazole-based 1,2,3-thiadiazoles structural against tobacco mosaic virus (TMV, anti-TMV) were evaluated [84]. The studies indicated that some obtained compounds (95-98; Figure 7) have higher anti-TMV activity (33.75-48.73%) than ribavirin at 100mg/mL concentration (33.23%) and comparable potency to ribavirin at 100 µg/mL. Structure 97 displayed the best protection effect among the synthesized derivatives as well as from the ribavirin-reference drug. Anti-TMV activity of synthesized scaffolds and reference drugs decreases in order of 98 > ninamycin >97 > 95 > 96 > ribavirin while the protection effect decreased in order of ninamycin > 97 > 96 > 95> ribavirin > 98. Compound 98 display a higher inhibition potential, i.e., 48.73% as compared to ninamycin and ribavirin. The SAR study showed that the 2-fluorophenyl substituent derivative 97 displayed the best protection effect among the synthesized congeners as well as from the ribavirin reference drug. The protection effect decreased in order of ninamycin > 2-fluorophenyl > cyclopropyl > isopropyl > ribavirin > 4-ethylphenyl. Overall the scaffold 97 proved to be a promising therapeutic agent, which has a better protection effect as well as the best anti-TMV activity [84]. Mao et al. reported the synthetic protocol to afford substituted methyl carbohydrazide-based 1,2,3-thiadiazoles and determined the anti-TMV activity. The thiophene containing carbohydrazide 1,2,3-thiadiazole (99; Figure 8) showed potent direct anti-TMV activity with 58.72% and 61.03% induction potencies at 50 µg/mL when compared with reference drugs, ninamycin and tiadinil. Both the standard reference drugs, ninamycin and tiadinil, exhibited anti-TMV activity (54.93% and 7.94%) and induction activity Mao et al. reported the synthetic protocol to afford substituted methyl carbohydrazidebased 1,2,3-thiadiazoles and determined the anti-TMV activity. The thiophene containing carbohydrazide 1,2,3-thiadiazole (99; Figure 8) showed potent direct anti-TMV activity with 58.72% and 61.03% induction potencies at 50 µg/mL when compared with reference drugs, ninamycin and tiadinil. Both the standard reference drugs, ninamycin and tiadinil, exhibited anti-TMV activity (54.93% and 7.94%) and induction activity (18.58% and 59.25%) respectively in vivo at 50 µg/mL concentration. The scaffold 99 showed remarkably and significant higher antiviral potential than the standard reference drugs. The excellent anti-TMV activity of analogue 99 was due to the presence of thiophene moiety as compare to all the other tested compounds. The structural motif 99 showed significantly higher induction activity (61.03%) more than the induction activities of reference drugs, ninamycin and tiadinil (18.58%) and (59.25%), respectively. So the derivative 99 proved to be a plant elicitor and anti-TMV agent simultaneously [108]. Mao et al. reported the synthetic protocol to afford substituted methyl carbohydrazide-based 1,2,3-thiadiazoles and determined the anti-TMV activity. The thiophene containing carbohydrazide 1,2,3-thiadiazole (99; Figure 8) showed potent direct anti-TMV activity with 58.72% and 61.03% induction potencies at 50 µg/mL when compared with reference drugs, ninamycin and tiadinil. Both the standard reference drugs, ninamycin and tiadinil, exhibited anti-TMV activity (54.93% and 7.94%) and induction activity (18.58% and 59.25%) respectively in vivo at 50 µg/mL concentration. The scaffold 99 showed remarkably and significant higher antiviral potential than the standard reference drugs. The excellent anti-TMV activity of analogue 99 was due to the presence of thiophene moiety as compare to all the other tested compounds. The structural motif 99 showed significantly higher induction activity (61.03%) more than the induction activities of reference drugs, ninamycin and tiadinil (18.58%) and (59.25%), respectively. So the derivative 99 proved to be a plant elicitor and anti-TMV agent simultaneously [108]. Another example of compounds with anti-TMV activity are structures 100 and 101 with a 1,3,4-oxadiazole ring (Figure 9) [109]. They showed potent curative, inactivation and protection effects against TMV. The derivative 100 displayed curative rate 54.1%, inactivation rate 90.3% and protection rate 52.8% while the compound 101 showed 47.1, 85.5 and 46.4% curative, inactivation and protection rates, respectively. The ningnanmycin was used as a standard reference drug, exhibiting a 56.1% curative rate, 92.5% inactivation rate and 59.3% protection rate. The incorporation of 1,3,4-oxadiazole moiety in the skeleton of 1,2,3-thiadiazoles significantly increased the anti-TMV activity [109].  Another example of compounds with anti-TMV activity are structures 100 and 101 with a 1,3,4-oxadiazole ring (Figure 9) [109]. They showed potent curative, inactivation and protection effects against TMV. The derivative 100 displayed curative rate 54.1%, inactivation rate 90.3% and protection rate 52.8% while the compound 101 showed 47.1, 85.5 and 46.4% curative, inactivation and protection rates, respectively. The ningnanmycin was used as a standard reference drug, exhibiting a 56.1% curative rate, 92.5% inactivation rate and 59.3% protection rate. The incorporation of 1,3,4-oxadiazole moiety in the skeleton of 1,2,3-thiadiazoles significantly increased the anti-TMV activity [109]. Mao et al. reported the synthetic protocol to afford substituted methyl carbohydrazide-based 1,2,3-thiadiazoles and determined the anti-TMV activity. The thiophene containing carbohydrazide 1,2,3-thiadiazole (99; Figure 8) showed potent direct anti-TMV activity with 58.72% and 61.03% induction potencies at 50 µg/mL when compared with reference drugs, ninamycin and tiadinil. Both the standard reference drugs, ninamycin and tiadinil, exhibited anti-TMV activity (54.93% and 7.94%) and induction activity (18.58% and 59.25%) respectively in vivo at 50 µg/mL concentration. The scaffold 99 showed remarkably and significant higher antiviral potential than the standard reference drugs. The excellent anti-TMV activity of analogue 99 was due to the presence of thiophene moiety as compare to all the other tested compounds. The structural motif 99 showed significantly higher induction activity (61.03%) more than the induction activities of reference drugs, ninamycin and tiadinil (18.58%) and (59.25%), respectively. So the derivative 99 proved to be a plant elicitor and anti-TMV agent simultaneously [108]. Another example of compounds with anti-TMV activity are structures 100 and 101 with a 1,3,4-oxadiazole ring (Figure 9) [109]. They showed potent curative, inactivation and protection effects against TMV. The derivative 100 displayed curative rate 54.1%, inactivation rate 90.3% and protection rate 52.8% while the compound 101 showed 47.1, 85.5 and 46.4% curative, inactivation and protection rates, respectively. The ningnanmycin was used as a standard reference drug, exhibiting a 56.1% curative rate, 92.5% inactivation rate and 59.3% protection rate. The incorporation of 1,3,4-oxadiazole moiety in the skeleton of 1,2,3-thiadiazoles significantly increased the anti-TMV activity [109].  Other promising anti-TMV agents 102 and 103 were presented by Zheng et al. (Figure 10) [83]. The substituted 1,2,3-thiadiazole-4-carboxamide scaffold 102 exhibited the best antiviral curative activity of 60 and 47%, at 500 and 100 µg/mL concentrations, while the standard tiadinil showed curative activity 58 and 46% at 500 and 100 µg/mL concentrations, respectively. Compound 103 showed its potent protective effect 76 and 71% at 500 and 100 µg/mL concentrations in comparison with the standard drug tiadinil, which displayed protective 75 and 57% at 500 and 100 µg/mL. The structure 103 marked a higher protective effect than the tiadinil and 102 at 100 µg/mL concentration. The enhanced protective potential of 103 was dose-dependent and due to the presence of hyroxyphenyl moiety. The fluorophenyl, chlorophenyl and hyroxyphenyl functionalities contributed to better efficacy that led to a future investigation to develop promising anti-TMV agents [83]. 500 and 100 µg/mL concentrations in comparison with the standard drug tiadinil, which displayed protective 75 and 57% at 500 and 100 µg/mL. The structure 103 marked a higher protective effect than the tiadinil and 102 at 100 µg/mL concentration. The enhanced protective potential of 103 was dose-dependent and due to the presence of hyroxyphenyl moiety. The fluorophenyl, chlorophenyl and hyroxyphenyl functionalities contributed to better efficacy that led to a future investigation to develop promising anti-TMV agents [83].

Anticancer Agents
Cancer has drawn the attention of today's medical science all over the world because it is the lethal, notably complex, most prominent and serious threat to human health. It forms the lump of uncontrolled growth cells called tumors or neoplasm tumor cells. The neoplasm malignant are diversified heterogeneous cells which have properties of rapid proliferation and capability to invade or spread to other parts of the body through the 500 and 100 µg/mL concentrations in comparison with the standard drug tiadinil, which displayed protective 75 and 57% at 500 and 100 µg/mL. The structure 103 marked a higher protective effect than the tiadinil and 102 at 100 µg/mL concentration. The enhanced protective potential of 103 was dose-dependent and due to the presence of hyroxyphenyl moiety. The fluorophenyl, chlorophenyl and hyroxyphenyl functionalities contributed to better efficacy that led to a future investigation to develop promising anti-TMV agents [83].

Anticancer Agents
Cancer has drawn the attention of today's medical science all over the world because it is the lethal, notably complex, most prominent and serious threat to human health. It forms the lump of uncontrolled growth cells called tumors or neoplasm tumor cells. The neoplasm malignant are diversified heterogeneous cells which have properties of rapid proliferation and capability to invade or spread to other parts of the body through the

Anticancer Agents
Cancer has drawn the attention of today's medical science all over the world because it is the lethal, notably complex, most prominent and serious threat to human health. It forms the lump of uncontrolled growth cells called tumors or neoplasm tumor cells. The neoplasm malignant are diversified heterogeneous cells which have properties of rapid proliferation and capability to invade or spread to other parts of the body through the bloodstream and lymphatic system. Most researchers have devoted their extensive research to developing effective anticancer agents, along with the employment and application of integrated surgical procedures, radiation therapy and chemotherapy [111,112]. Great advances and many discoveries in the development of a large quantity of anticancer therapeutics such as carboplatin (105) cisplatin (106) [113][114][115], anastrozole (107) [116,117] and doxorubicin (108) (Figure 12), etc., have been made over the past 60 years [118][119][120][121].
Noteworthy are the 4,5-diaryl-1,2,3-thiadiazole derivatives obtained by Wu et al. due to their method of synthesis and anticancer properties [122], and results pointed out that compounds 109 and 110 are the lead compounds by exhibiting favorable activity ( Figure 13). Growth inhibition rate of tumor cells (obtained from mice S180) by derivative 109 at a dose of 40 mg/kg administrated for 5 days reached 81.0%, while compound 110 displayed a tumor suppression efficacy of 64.2% (at 100 mg/kg of dose administered to mice for five days). These effects were compared with the standard reference CA-4 (combretastatin A-4), which showed a 64.2% antitumor effect at a dose of 40 mg/kg used for 4 days in a mouse model. The SAR study indicated that the reason of the highest antitumor activity of structural motif 109 than reference drug CA-4 and derivative 110 was because of OMe group at C-4 and H at C-3 of 5-phenyl ring of 1,2,3-thiadiazole, while the replacement of hydrogen at C-3 with the nitro group dropped the antitumor activity of derivative 110. The scaffold 109 could be a promising candidate due to its lower cytotoxicity and excellent antitumor effect [122].
Appl. Sci. 2021, 11, x FOR PEER REVIEW 15 of 30 bloodstream and lymphatic system. Most researchers have devoted their extensive research to developing effective anticancer agents, along with the employment and application of integrated surgical procedures, radiation therapy and chemotherapy [111,112]. Great advances and many discoveries in the development of a large quantity of anticancer therapeutics such as carboplatin (105) cisplatin (106) [113][114][115], anastrozole (107) [116,117] and doxorubicin (108) (Figure 12), etc., have been made over the past 60 years [118][119][120][121]. Noteworthy are the 4,5-diaryl-1,2,3-thiadiazole derivatives obtained by Wu et al. due to their method of synthesis and anticancer properties [122], and results pointed out that compounds 109 and 110 are the lead compounds by exhibiting favorable activity ( Figure 13). Growth inhibition rate of tumor cells (obtained from mice S180) by derivative 109 at a dose of 40 mg/kg administrated for 5 days reached 81.0%, while compound 110 displayed a tumor suppression efficacy of 64.2% (at 100 mg/kg of dose administered to mice for five days). These effects were compared with the standard reference CA-4 (combretastatin A-4), which showed a 64.2% antitumor effect at a dose of 40 mg/kg used for 4 days in a mouse model. The SAR study indicated that the reason of the highest antitumor activity of structural motif 109 than reference drug CA-4 and derivative 110 was because of OMe group at C-4 and H at C-3 of 5-phenyl ring of 1,2,3-thiadiazole, while the replacement of hydrogen at C-3 with the nitro group dropped the antitumor activity of derivative 110. The scaffold 109 could be a promising candidate due to its lower cytotoxicity and excellent antitumor effect [122].  Noteworthy are the 4,5-diaryl-1,2,3-thiadiazole derivatives obtained by Wu et al. due to their method of synthesis and anticancer properties [122], and results pointed out that compounds 109 and 110 are the lead compounds by exhibiting favorable activity ( Figure 13). Growth inhibition rate of tumor cells (obtained from mice S180) by derivative 109 at a dose of 40 mg/kg administrated for 5 days reached 81.0%, while compound 110 displayed a tumor suppression efficacy of 64.2% (at 100 mg/kg of dose administered to mice for five days). These effects were compared with the standard reference CA-4 (combretastatin A-4), which showed a 64.2% antitumor effect at a dose of 40 mg/kg used for 4 days in a mouse model. The SAR study indicated that the reason of the highest antitumor activity of structural motif 109 than reference drug CA-4 and derivative 110 was because of OMe group at C-4 and H at C-3 of 5-phenyl ring of 1,2,3-thiadiazole, while the replacement of hydrogen at C-3 with the nitro group dropped the antitumor activity of derivative 110. The scaffold 109 could be a promising candidate due to its lower cytotoxicity and excellent antitumor effect [122].    Cikotiene et al. reported the synthetic protocol to achieve the substituted 4,5-diaryl-1,2,3-thiadiazoles as Hsp90 chaperone protein inhibitors. This protein plays a significant part in developing tumor cells, so its inhibition is the main target of many anticancer drugs. The Hsp90 chaperone stabilizes a number of proteins that are essential for the growth of tumors, due to which researchers all over the world are interested in the development of Hsp90 inhibitors which would be investigated as anticancer agents. In the group of tested derivatives, structure 113 deserves special attention as an inhibitor of cancer cells with GI50 value of 0.69 µM for U2OS (osteosarcoma) cells and 0.70 µM for HeLa (cervical carcinoma) cells (Figure 15) [124]. Isothermal titration calorimetry was used to determine the binding affinity of compound (113) to Hsp90F and Hsp90N. The Cikotiene et al. reported the synthetic protocol to achieve the substituted 4,5-diaryl-1,2,3-thiadiazoles as Hsp90 chaperone protein inhibitors. This protein plays a significant part in developing tumor cells, so its inhibition is the main target of many anticancer drugs. The Hsp90 chaperone stabilizes a number of proteins that are essential for the growth of tumors, due to which researchers all over the world are interested in the development of Hsp90 inhibitors which would be investigated as anticancer agents. In the group of tested derivatives, structure 113 deserves special attention as an inhibitor of cancer cells with GI 50 value of 0.69 µM for U2OS (osteosarcoma) cells and 0.70 µM for HeLa (cervical carcinoma) cells ( Figure 15) [124]. Isothermal titration calorimetry was used to determine the binding affinity of compound (113) to Hsp90F and Hsp90N. The derivative (39)  Cikotiene et al. reported the synthetic protocol to achieve the substituted 4,5-diaryl-1,2,3-thiadiazoles as Hsp90 chaperone protein inhibitors. This protein plays a significant part in developing tumor cells, so its inhibition is the main target of many anticancer drugs. The Hsp90 chaperone stabilizes a number of proteins that are essential for the growth of tumors, due to which researchers all over the world are interested in the development of Hsp90 inhibitors which would be investigated as anticancer agents. In the group of tested derivatives, structure 113 deserves special attention as an inhibitor of cancer cells with GI50 value of 0.69 µM for U2OS (osteosarcoma) cells and 0.70 µM for HeLa (cervical carcinoma) cells ( Figure 15) [124]. Isothermal titration calorimetry was used to determine the binding affinity of compound (113) to Hsp90F and Hsp90N. The derivative (39) acted as a binder to both Hsp90N andHsp90F with the observed Kd of about 42 nM and 37 nM, while for the reference compound17-AAG [17-(allylamino)-17-demethoxygeldanamycin] Kd was 200 nM and 240 nM, respectively [124]. Synthesized by Cui et al., dehydroepiandrosterone derivatives of thiadiazoles were investigated against T47D and HAF cell lines for their antitumor activity applying the sulforhodamine B (SRB) assay. In this group of compounds, derivative 114 ( Figure 16) focuses particular attention, due to its strong antitumor and antimetastatic activities, in vitro and in vivo. Its IC50 value for T47D cells was 0.058 ± 0.016 µM and for HAF cells IC50 = 21.1 ± 5.06 µM. Moreover, the selectivity of compound 114 (SI = 364) was 214 folds better than adriamycin (positive control) (ADM; SI = 1.7). The SAR study showed that the introduction of 1,2,3-thiadiazole and D-proline chemical entities in derivative 114 significantly enhanced antiproliferative activity than the parent DHEA. The SI of scaffold 114 was 214 folds better than SI of ADM standard drugs. The derivative 114 could be used as the promising and novel class of anticancer agent due to its low cytotoxicity, high selectivity index and excellent antitumor and antiproliferative activities ( Figure 16) [125]. Synthesized by Cui et al., dehydroepiandrosterone derivatives of thiadiazoles were investigated against T47D and HAF cell lines for their antitumor activity applying the sulforhodamine B (SRB) assay. In this group of compounds, derivative 114 ( Figure 16) focuses particular attention, due to its strong antitumor and antimetastatic activities, in vitro and in vivo. Its IC 50 value for T47D cells was 0.058 ± 0.016 µM and for HAF cells IC 50 = 21.1 ± 5.06 µM. Moreover, the selectivity of compound 114 (SI = 364) was 214 folds better than adriamycin (positive control) (ADM; SI = 1.7). The SAR study showed that the introduction of 1,2,3-thiadiazole and D-proline chemical entities in derivative 114 significantly enhanced antiproliferative activity than the parent DHEA. The SI of scaffold 114 was 214 folds better than SI of ADM standard drugs. The derivative 114 could be used as the promising and novel class of anticancer agent due to its low cytotoxicity, high selectivity index and excellent antitumor and antiproliferative activities ( Figure 16) [125].
Cikotiene et al. reported the synthetic protocol to achieve the substituted 4,5-diaryl-1,2,3-thiadiazoles as Hsp90 chaperone protein inhibitors. This protein plays a significant part in developing tumor cells, so its inhibition is the main target of many anticancer drugs. The Hsp90 chaperone stabilizes a number of proteins that are essential for the growth of tumors, due to which researchers all over the world are interested in the development of Hsp90 inhibitors which would be investigated as anticancer agents. In the group of tested derivatives, structure 113 deserves special attention as an inhibitor of cancer cells with GI50 value of 0.69 µM for U2OS (osteosarcoma) cells and 0.70 µM for HeLa (cervical carcinoma) cells ( Figure 15) [124]. Isothermal titration calorimetry was used to determine the binding affinity of compound (113) to Hsp90F and Hsp90N. The derivative (39) acted as a binder to both Hsp90N andHsp90F with the observed Kd of about 42 nM and 37 nM, while for the reference compound17-AAG [17-(allylamino)-17-demethoxygeldanamycin] Kd was 200 nM and 240 nM, respectively [124]. Synthesized by Cui et al., dehydroepiandrosterone derivatives of thiadiazoles were investigated against T47D and HAF cell lines for their antitumor activity applying the sulforhodamine B (SRB) assay. In this group of compounds, derivative 114 ( Figure 16) focuses particular attention, due to its strong antitumor and antimetastatic activities, in vitro and in vivo. Its IC50 value for T47D cells was 0.058 ± 0.016 µM and for HAF cells IC50 = 21.1 ± 5.06 µM. Moreover, the selectivity of compound 114 (SI = 364) was 214 folds better than adriamycin (positive control) (ADM; SI = 1.7). The SAR study showed that the introduction of 1,2,3-thiadiazole and D-proline chemical entities in derivative 114 significantly enhanced antiproliferative activity than the parent DHEA. The SI of scaffold 114 was 214 folds better than SI of ADM standard drugs. The derivative 114 could be used as the promising and novel class of anticancer agent due to its low cytotoxicity, high selectivity index and excellent antitumor and antiproliferative activities ( Figure 16) [125].

Insecticidal Agents
Insecticides are the designed substances of either chemical or biological origin that used to regulate the insect behaviour, control insects, cause death, dysfunction and moving away [126,127]. Some of the insecticidal agents, such as tebufenozide (115) act as molting hormones primarily against caterpillar pests [128]; imidacloprid (116) is the most wellknown broad spectrum insecticide, which used as an insect neurotoxin [129][130][131], and neuroactive pymetrozine (117) is a novel class of pyridineazomethine insecticide used for the control of aphids and whiteflies in crop fields ( Figure 17) [132].
An interesting example of 1,2,3-thiadiazole derivatives with insecticidal properties are two groups of N-tert-butyl-N,N -diacylhydrazines obtained by Wang et al. [29] and tested their activity against Plutella xylostella L. and Culex pipiens pallens. Derivative 118 (Figure 18) displayed remarkable and significantly the highest insecticidal potential (79% mortality at 200 µg/mL) against Plutella xylostella L., while 119 exhibited 68% mortality against the same insects at concentration 200 µg/mL. Insecticidal activity of reference agent, i.e., tebufenozide, was 40%. The scaffold 118 displayed excellent and the highest insecticidal potency, 79% more than the insecticidal potencies of reference drug tebufenozide (40%) and derivative 119 (68%). The EWD group chloro increased the insecticidal activity of scaffold 118, while ED group methyl decreased the insecticidal potency of scaffold 119 [29].

Insecticidal Agents
Insecticides are the designed substances of either chemical or biological origin that used to regulate the insect behaviour, control insects, cause death, dysfunction and moving away [126,127]. Some of the insecticidal agents, such as tebufenozide (115) act as molting hormones primarily against caterpillar pests [128]; imidacloprid (116) is the most well-known broad spectrum insecticide, which used as an insect neurotoxin [129][130][131], and neuroactive pymetrozine (117) is a novel class of pyridineazomethine insecticide used for the control of aphids and whiteflies in crop fields ( Figure 17) [132]. An interesting example of 1,2,3-thiadiazole derivatives with insecticidal properties are two groups of N-tert-butyl-N,N'-diacylhydrazines obtained by Wang et al. [29] and tested their activity against Plutella xylostella L. and Culex pipiens pallens. Derivative 118 ( Figure 18) displayed remarkable and significantly the highest insecticidal potential (79% mortality at 200 µg/mL) against Plutella xylostella L., while 119 exhibited 68% mortality against the same insects at concentration 200 µg/mL. Insecticidal activity of reference agent, i.e., tebufenozide, was 40%. The scaffold 118 displayed excellent and the highest insecticidal potency, 79% more than the insecticidal potencies of reference drug tebufenozide (40%) and derivative 119 (68%). The EWD group chloro increased the insecticidal activity of scaffold 118, while ED group methyl decreased the insecticidal potency of scaffold 119 [29]. Zhang et al. designed the (E)-β-farnesene based carboxamides of thiadiazoles and checked their aphicidal behavior against Myzus persicae [133]. The three compound 120-122 ( Figure 19) exhibited LC50 values of 33.4 µg/mL, 50.2 µg/mL and 61.8 µg/mL, respectively. The 1,2,3-thiadiazole carboxamide analogues showed significantly higher aphicidal activity than (E)-ß-farnesene, but lesser insecticidal activity than pymetrozine insecticide (LC50 = 7.1 µg/mL). It was observed that fluoro or difluoro groups on phenyl moiety enhanced the aphicidal potential significantly in novel chemical entities of Eβf 1,2,3-thiadiazole 120 and 121 while the methyl substitution led to lower aphicidal activity of scaffold 122 [133]. An interesting example of 1,2,3-thiadiazole derivatives with insecticidal properties are two groups of N-tert-butyl-N,N'-diacylhydrazines obtained by Wang et al. [29] and tested their activity against Plutella xylostella L. and Culex pipiens pallens. Derivative 118 ( Figure 18) displayed remarkable and significantly the highest insecticidal potential (79% mortality at 200 µg/mL) against Plutella xylostella L., while 119 exhibited 68% mortality against the same insects at concentration 200 µg/mL. Insecticidal activity of reference agent, i.e., tebufenozide, was 40%. The scaffold 118 displayed excellent and the highest insecticidal potency, 79% more than the insecticidal potencies of reference drug tebufenozide (40%) and derivative 119 (68%). The EWD group chloro increased the insecticidal activity of scaffold 118, while ED group methyl decreased the insecticidal potency of scaffold 119 [29]. Zhang et al. designed the (E)-β-farnesene based carboxamides of thiadiazoles and checked their aphicidal behavior against Myzus persicae [133]. The three compound 120-122 ( Figure 19) exhibited LC50 values of 33.4 µg/mL, 50.2 µg/mL and 61.8 µg/mL, respectively. The 1,2,3-thiadiazole carboxamide analogues showed significantly higher aphicidal activity than (E)-ß-farnesene, but lesser insecticidal activity than pymetrozine insecticide (LC50 = 7.1 µg/mL). It was observed that fluoro or difluoro groups on phenyl moiety enhanced the aphicidal potential significantly in novel chemical entities of Eβf 1,2,3-thiadiazole 120 and 121 while the methyl substitution led to lower aphicidal activity of scaffold 122 [133]. Zhang et al. designed the (E)-β-farnesene based carboxamides of thiadiazoles and checked their aphicidal behavior against Myzus persicae [133]. The three compound 120-122 ( Figure 19) exhibited LC 50 values of 33.4 µg/mL, 50.2 µg/mL and 61.8 µg/mL, respectively. The 1,2,3-thiadiazole carboxamide analogues showed significantly higher aphicidal activity than (E)-ß-farnesene, but lesser insecticidal activity than pymetrozine insecticide (LC 50 = 7.1 µg/mL). It was observed that fluoro or difluoro groups on phenyl moiety enhanced the aphicidal potential significantly in novel chemical entities of Eβf 1,2,3-thiadiazole 120 and 121 while the methyl substitution led to lower aphicidal activity of scaffold 122 [133]. Pyrazole oxime derivatives, as a new Fenpyroximate analogue bearing a thiadiazole moiety, were synthesized by Dai et al. and then their insecticidal, acaricidal and cytotoxic activities were examined. The best insecticidal properties possessed oximes 123 and 124 ( Figure 20) against Aphis craccivora at 100 µg/mL with 90% of the mortality rate. The structure-activity relationship study revealed that due to the insertion of F-and Me-groups at p-position of phenoxy moiety attached to the pyrazole oxime 123 and 124 displayed good insecticidal activities but slightly lower than commercial drug imidacloprid [134]. Pyrazole oxime derivatives, as a new Fenpyroximate analogue bearing a thiadiazole moiety, were synthesized by Dai et al. and then their insecticidal, acaricidal and cytotoxic activities were examined. The best insecticidal properties possessed oximes 123 and 124 ( Figure 20) against Aphis craccivora at 100 µg/mL with 90% of the mortality rate. The structure-activity relationship study revealed that due to the insertion of F-and Me-groups at p-position of phenoxy moiety attached to the pyrazole oxime 123 and 124 displayed good insecticidal activities but slightly lower than commercial drug imidacloprid [134]. moiety, were synthesized by Dai et al. and then their insecticidal, acaricidal and cytotoxic activities were examined. The best insecticidal properties possessed oximes 123 and 124 ( Figure 20) against Aphis craccivora at 100 µg/mL with 90% of the mortality rate. The structure-activity relationship study revealed that due to the insertion of F-and Me-groups at p-position of phenoxy moiety attached to the pyrazole oxime 123 and 124 displayed good insecticidal activities but slightly lower than commercial drug imidacloprid [134]. Another interesting example of insecticidal compounds are hybrids of substituted triazole and 1,2,3-thiadizole scaffold that were investigated for their activity against Aphis laburni and TMV by Li et al. [135]. Preliminary bioassays indicated compounds 125 and 126 ( Figure 21) as lead compounds by depicting enhanced activity against Aphis laburni at 100mg/mL (mortality ≥ 95%) while the derivative 127 represent the least active compound (due to CF3 substituted triazole ring) that displayed only 25.25% mortality. The structure-activity study indicated that scaffolds with aromatic moieties attached to the carbonyl carbon of triazole ring have higher insecticidal activity than scaffolds with alkyl moieties [135]. Another interesting example of insecticidal compounds are hybrids of substituted triazole and 1,2,3-thiadizole scaffold that were investigated for their activity against Aphis laburni and TMV by Li et al. [135]. Preliminary bioassays indicated compounds 125 and 126 ( Figure 21) as lead compounds by depicting enhanced activity against Aphis laburni at 100mg/mL (mortality ≥ 95%) while the derivative 127 represent the least active compound (due to CF 3 substituted triazole ring) that displayed only 25.25% mortality. The structure-activity study indicated that scaffolds with aromatic moieties attached to the carbonyl carbon of triazole ring have higher insecticidal activity than scaffolds with alkyl moieties [135]. moiety, were synthesized by Dai et al. and then their insecticidal, acaricidal and cytotoxic activities were examined. The best insecticidal properties possessed oximes 123 and 124 ( Figure 20) against Aphis craccivora at 100 µg/mL with 90% of the mortality rate. The structure-activity relationship study revealed that due to the insertion of F-and Me-groups at p-position of phenoxy moiety attached to the pyrazole oxime 123 and 124 displayed good insecticidal activities but slightly lower than commercial drug imidacloprid [134]. Another interesting example of insecticidal compounds are hybrids of substituted triazole and 1,2,3-thiadizole scaffold that were investigated for their activity against Aphis laburni and TMV by Li et al. [135]. Preliminary bioassays indicated compounds 125 and 126 ( Figure 21) as lead compounds by depicting enhanced activity against Aphis laburni at 100mg/mL (mortality ≥ 95%) while the derivative 127 represent the least active compound (due to CF3 substituted triazole ring) that displayed only 25.25% mortality. The structure-activity study indicated that scaffolds with aromatic moieties attached to the carbonyl carbon of triazole ring have higher insecticidal activity than scaffolds with alkyl moieties [135].

Amoebicidal Agents
A parasitic disease caused by a protozoa Entamoeba histolytica is known as amoebiasis. E. histolytica has infected 40 to 50 million people worldwide and led to the development of amoebic colitis or extraintestinal abscess that has resulted in 100,000 deaths annually [136][137][138]. The tissue amoebiasis is treated by different drugs such as metronidazole, chloroquine, tinidazole, dehydroemetine and nitazoxanide, while the diloxanide furoate and iodoquinoline drugs are used to treat luminal infections ( Figure 22) [139][140][141][142][143].

Plant Activator Agents
Plant activators are synthetic or natural chemicals entities that protect plants from different pathogens. Among them, pyrimidin-type plant activator 2 (PPA2 133; Figure 24) significantly enhanced plant defense system against bacterial infections unlikely traditional commercially available plant activators (INA 134, BABA 135, BHT 7; Figure 24). Plant activators not only showed their therapeutic potential against wide variety of pathogens but also increased growth of plants, rate of photosynthesis and overall yield of crops [144][145][146][147][148].

Plant Activator Agents
Plant activators are synthetic or natural chemicals entities that protect plants from different pathogens. Among them, pyrimidin-type plant activator 2 (PPA2 133; Figure 24) significantly enhanced plant defense system against bacterial infections unlikely traditional commercially available plant activators (INA 134, BABA 135, BHT 7; Figure 24). Plant activators not only showed their therapeutic potential against wide variety of pathogens but also increased growth of plants, rate of photosynthesis and overall yield of crops [144][145][146][147][148].

Fungicidal Agents
The chemical agents that have the potential to control and eradicate fungal infections are termed as fungicides or antifungal drugs [149]. The commercial antifungal agents are chlorothalonil (65)

Fungicidal Agents
The chemical agents that have the potential to control and eradicate fungal infections are termed as fungicides or antifungal drugs [149]. The commercial antifungal agents are chlorothalonil (65) which is a non-systemic fungicide [150,151], fluconazole

Fungicidal Agents
The chemical agents that have the potential to control and eradicate fungal infections are termed as fungicides or antifungal drugs [149]. The commercial antifungal agents are chlorothalonil (65) which is a non-systemic fungicide [150,151], fluconazole (66) [152] and ketoconazole (67)

Fungicidal Agents
The chemical agents that have the potential to control and eradicate fungal infections are termed as fungicides or antifungal drugs [149]. The commercial antifungal agents are chlorothalonil (65) which is a non-systemic fungicide [150,151], fluconazole (66) [152] and ketoconazole (67) (Figure 26) [153]. As the first example, it is worth bring up oxadiazoles containing thiadiazole derivatives [154]. In this group, two oxadiazole derivatives 141 and 142 ( Figure 27) displayed the best antifungal activity against Puccinia triticina at a concentration of 500 µg/mL. Both structures showed a remarkable high growth inhibition activity (98 and 83%, respectively) which was slighter lower than the standard drug chlorothalonil with 100% fungal As the first example, it is worth bring up oxadiazoles containing thiadiazole derivatives [154]. In this group, two oxadiazole derivatives 141 and 142 ( Figure 27) displayed the best antifungal activity against Puccinia triticina at a concentration of 500 µg/mL. Both structures showed a remarkable high growth inhibition activity (98 and 83%, respectively) which was slighter lower than the standard drug chlorothalonil with 100% fungal growth inhibition activity. The remarkable high and excellent antifungal activity of scaffold 141 could lead to the development of novel oxadiazole-based 1,2,3-thiadiazole fungicides [154].
Appl. Sci. 2021, 11, x FOR PEER REVIEW 21 of growth inhibition activity. The remarkable high and excellent antifungal activity scaffold 141 could lead to the development of novel oxadiazole-based 1,2,3-thiadiazo fungicides [154]. Another example of compounds with good antifungal activities are new structur designed by Sun et al., which are 1,2,4-triazole derivatives substituted with 1,2,3-thiadiazole ring [82]. One of the synthesized compounds 143 (Figure 28), exhibite remarkably high fungicidal 93.19% against Corynespora cassiicola, while reference com pounds iprodione, validamycin and topsin-M possessed 78.20, 53.52 and 78.75% ant fungal activity, respectively. The authors declared that compound containing phen group on triazole ring 143 exhibited higher activity, however, the results were differe in the case of Pseudoperonospora cubensis as compound 144 containing cyclopropyl grou displayed higher activity than that of 143. The most active compound with regard Pseudoperonospora cubensis was 144, which inhibited the growth of this pathogen 81.62%. However, SAR analysis did not clear the results against pseudomonas syringae p Lachrymans. Both the scaffolds showed excellent and the highest antifungal potential tha all three commercial reference drugs that will lead to the development of promising a tifungal agents [82]. Another example of compounds with good antifungal activities are new structures designed by Sun et al., which are 1,2,4-triazole derivatives substituted with a 1,2,3-thiadiazole ring [82]. One of the synthesized compounds 143 (Figure 28), exhibited remarkably high fungicidal 93.19% against Corynespora cassiicola, while reference compounds iprodione, validamycin and topsin-M possessed 78.20, 53.52 and 78.75% antifungal activity, respectively. The authors declared that compound containing phenyl group on triazole ring 143 exhibited higher activity, however, the results were different in the case of Pseudoperonospora cubensis as compound 144 containing cyclopropyl group displayed higher activity than that of 143. The most active compound with regard to Pseudoperonospora cubensis was 144, which inhibited the growth of this pathogen in 81.62%. However, SAR analysis did not clear the results against pseudomonas syringae pv. Lachrymans. Both the scaffolds showed excellent and the highest antifungal potential than all three commercial reference drugs that will lead to the development of promising antifungal agents [82].
in the case of Pseudoperonospora cubensis as compound 144 containing cyclopropyl group displayed higher activity than that of 143. The most active compound with regard to Pseudoperonospora cubensis was 144, which inhibited the growth of this pathogen in 81.62%. However, SAR analysis did not clear the results against pseudomonas syringae pv. Lachrymans. Both the scaffolds showed excellent and the highest antifungal potential than all three commercial reference drugs that will lead to the development of promising antifungal agents [82]. Less antifungal activity was observed in the derivative 145 ( Figure 29)   Less antifungal activity was observed in the derivative 145 ( Figure 29) Figure 30) exhibited the best fungicidal inhibition activity 93.0% for FO, 84.9% for BC, 77.8% for PS, 75.8% for PI, 75.0% for GZ, 62.1% for CA, 50.0% for CL, 40.5% for PP, 34.4% for AS and 33.3% for CB. The results of the antifungal study showed that fused 1,2,4-triazolo [1,3,4]thiadiazole led to the development of wide-spectrum antifungal agents. [156].   Figure 30) exhibited the best fungicidal inhibition activity 93.0% for FO, 84.9% for BC, 77.8% for PS, 75.8% for PI, 75.0% for GZ, 62.1% for CA, 50.0% for CL, 40.5% for PP, 34.4% for AS and 33.3% for CB. The results of the antifungal study showed that fused 1,2,4-triazolo [1,3,4]thiadiazole led to the development of wide-spectrum antifungal agents [156].

Conclusions
The review has uncovered 1,2,3-thiadiazole is a unique heterocyclic structural motif and privileged template in the field of medicinal chemistry, specifically its antiviral profile, to attract the researchers/scientists to plan and create novel, target-based and advanced 1,2,3-thiadiazole derivatives. A broad pharmaceutical profile and biological properties such as fungicidal, antiviral, insecticidal, amoebicidal, anticancer and plant activators, etc. are shown along with a structure-activity relationship that will prompt potential pharmaceutical agents. In this review, we have tried to outline and summarize different synthetic approaches and strategies along with detailed modifications in substituents (structure-activity relationship). This review represents fruitful matrix that will

Conclusions
The review has uncovered 1,2,3-thiadiazole is a unique heterocyclic structural motif and privileged template in the field of medicinal chemistry, specifically its antiviral profile, to attract the researchers/scientists to plan and create novel, target-based and advanced 1,2,3-thiadiazole derivatives. A broad pharmaceutical profile and biological properties such as fungicidal, antiviral, insecticidal, amoebicidal, anticancer and plant activators, etc. are shown along with a structure-activity relationship that will prompt potential pharmaceutical agents. In this review, we have tried to outline and summarize different synthetic approaches and strategies along with detailed modifications in substituents (structure-activity relationship). This review represents fruitful matrix that will help the researchers to develop lead compounds in different biological domains.