Synthesis and Antimicrobial Activity of New Heteroaryl(aryl) Thiazole Derivatives Molecular Docking Studies

Herein, we report the design, synthesis, and evaluation of the antimicrobial activity of new heteroaryl (aryl) thiazole derivatives. The design was based on a molecular hybridization approach. The in vitro evaluation revealed that these compounds demonstrated moderate antibacterial activity. The best activity was achieved for compound 3, with MIC and MBC in the range of 0.23–0.7 and 0.47–0.94 mg/mL, respectively. Three compounds (2, 3, and 4) were tested against three resistant strains, namely methicillin resistant Staphylococcus aureus, P. aeruginosa, and E. coli, which showed higher potential than the reference drug ampicillin. Antifungal activity of the compounds was better with MIC and MFC in the range of 0.06–0.47 and 0.11–0.94 mg/mL, respectively. The best activity was observed for compound 9, with MIC at 0.06–0.23 mg/mL and MFC at 0.11–0.47 mg/mL. According to docking studies, the predicted inhibition of the E. coli MurB enzyme is a putative mechanism of the antibacterial activity of the compounds, while inhibition of 14a-lanosterol demethylase is probably the mechanism of their antifungal activity.

Sulfonamides are known as broad spectrum antimicrobial agents against Gram-positive and Gram-negative bacterial strains. These agents have low cost, low toxicity, and special activity against bacterial diseases. Sulfisoxazole, sulfamethizole, sulfamethoxazole, and sulfaphenazole are only some examples for the treatment of a diversity of bacterial infections.
Another example is the diuretic drug, chlorthalidone, which is used to treat hypertension or edema caused by heart failure, renal failure, hepatic cirrhosis, and estrogen therapy, as well as silver sulfadiazine, a topical sulfonamide antibiotic approved for the treatment of burns. Therefore, the design and development of hybrid molecules containing thiazolidinone phtalazine and thiazole cores, as well as sulfonamide groups, is a promising route in the search for novel antimicrobial agents. Molecular hybridization based on the amalgamation of two or more substitutions [54] is one of the new approaches in drug design. Hybridization is mainly aimed to improve the activity profile and to reduce undesired side effects [55].
Taking all of this information into account and based on our previous results [56][57][58], we designed and synthesized new derivatives incorporating thiazole, phtalazine moieties, and the sulfonamide group in the frame of one molecule.

Chemistry
In this work, we have described the synthesis of three structural series of new thiazole derivatives and presented the results of a study of their antibacterial and antifungal activity against a number of bacterial and fungal pathogens. All the target compounds were synthesized via four routes, as outlined in Scheme 1. Sulfonamides are known as broad spectrum antimicrobial agents against Gram-positive and Gram-negative bacterial strains. These agents have low cost, low toxicity, and special activity against bacterial diseases. Sulfisoxazole, sulfamethizole, sulfamethoxazole, and sulfaphenazole are only some examples for the treatment of a diversity of bacterial infections.
Another example is the diuretic drug, chlorthalidone, which is used to treat hypertension or edema caused by heart failure, renal failure, hepatic cirrhosis, and estrogen therapy, as well as silver sulfadiazine, a topical sulfonamide antibiotic approved for the treatment of burns. Therefore, the design and development of hybrid molecules containing thiazolidinone phtalazine and thiazole cores, as well as sulfonamide groups, is a promising route in the search for novel antimicrobial agents. Molecular hybridization based on the amalgamation of two or more substitutions [54] is one of the new approaches in drug design. Hybridization is mainly aimed to improve the activity profile and to reduce undesired side effects [55].
Taking all of this information into account and based on our previous results [56][57][58], we designed and synthesized new derivatives incorporating thiazole, phtalazine moieties, and the sulfonamide group in the frame of one molecule.

Chemistry
In this work, we have described the synthesis of three structural series of new thiazole derivatives and presented the results of a study of their antibacterial and antifungal activity against a number of bacterial and fungal pathogens. All the target compounds were synthesized via four routes, as outlined in Scheme 1.
Compounds 4-7 were obtained by the reaction of nucleophilic substitution of the chlorine atom in 1-chloro-4-R-phthalazines. The best solvent for this reaction is methyl cellosolve, both in terms of yields and the purity of the reaction products. We especially note that the addition of ammonia for the conversion of product salts into bases should be carried out when the temperature of the reaction mixture is about 100 • C, since neutralization at ordinary temperature takes a very long time and does not guarantee the complete conversion of salts into bases. Compound 3 was synthesized using our rather unusual recyclization reaction of 1chloromethyl-3,4-dihydroisoquinolines under the action of thioamides and thioureas. . In this article, the possibility of such recycling was confirmed by us, including using X-ray diffraction analysis and NMR spectroscopy (a one-proton singlet of the thiazole ring (H-5 ) of all the compounds described in the article is observed in the region of 6.85-6.98 ppm).
In the present work, the spectra of the studied compounds are also characterized by the presence in their aromatic region of a one-proton singlet of the thiazole ring (H-5 ) in the region of 6.01-7.04 ppm; in the case of compound 3, this signal was detected at 7.44 ppm.
In the 1 H NMR spectra of compounds 1, 2, and 8 in deuterochloroform, the signals of the methyl groups of the isopropyl group are located in the upfield part of the spectra (1.21-1.28 ppm).
The amide proton NHCO in compounds 1 and 2 appears as a multiplet in the region 8. 21-8.31, and in compound 8 it appears as a singlet at 8.08.
Compounds 4-7 contain two singlets: at 12.46-12.48 ppm of the sulfamide group NHSO 2 and at 9.42-9.49 ppm of the NH group.

Antibacterial Activity
Synthesized compounds were tested for their antibacterial activity against a panel of six bacteria, using a microdilution method for the determination of minimal inhibitory and minimal bactericidal concentrations (MIC and MBC, respectively). The antibacterial activity of tested compounds was moderate to good, with MIC ranging from 0.17 to >3.75 mg/mL and MBC at 0.23->3.75 mg/mL, as presented in Table 1. The order of activity can be presented as follows: 3 > 2 > 9 > 4 > 5 > 7 > 8 > 1 > 6. The best activity was achieved for compound 3 with MIC and MBC at 0.23-0.70 mg/mL and 0.47-0.94 mg/mL, respectively. The most sensitive bacterium appeared to be B. cereus, whereas E. coli was the most resistant one.
Compound 4 exhibited the best activity among the compounds tested against E. coli, with MIC/MBC at 0.17/0.23 mg/mL, while compound 9 showed the same good activity against B. cereus and S. Typhimurium. Compounds 1 and 8 exhibited in vitro activity with MIC and MBC at 0.23/0.47 mg/mL against E. cloacae, compounds 3 and 5 against E. coli, while compound 3 also displayed good activity against S. Typhimurium. In general, these compounds showed moderate to low activity.
The study of structure-activity relationships revealed that the presence of 2-(3,4dimethoxyphenyl)ethanamine as substituent at position 4 and phenol at position 2 of the thiazole ring (3) are beneficial for antibacterial activity. Among the group of compounds 1, 2, and 8, the more favorable effect was observed in the case of 2-methylisoquinolin-1(2H)-one substituent connected via N-propylpropionamide with the thiazole ring (2). The presence of phenylphthalazine (4) as the substituent was positive in the case of compounds 4-7. Introduction of 4-Cl substituent to phenylphthalazine (5) decreased a little activity, while the presence of the 4-OMe group decreased more activity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds. tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.    tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds. tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.  tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.  tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.  tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.  tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.   tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.   tivity. Finally, replacement of phenylphtalazine by 1-methylphtalazine (6) was detrimental for this group of compounds and in general for all tested compounds.   The evaluation of three of the most active compounds (2, 3, 4) against three resistant strains, namely methicillin-resistant Staphylococcus aureus (MRSA), P. aeruginosa, and E. coli, revealed that all compounds were found to be more potent against MRSA than ampicillin and streptomycin, which did not show a bactericidal effect. Compound 4 also seems to be more active than ampicillin against P. aeruginosa strain, but no compound was more active than the reference drug against E. coli ( Table 2). The compounds also were evaluated for their ability to inhibit the biofilm formation. Unfortunately, no compound showed good activity.

Antifungal Activity
Synthesized thiazolyl derivatives (1-9) were evaluated for their antifungal activity. For the determination of minimal inhibitory/fungicidal activity, the microdilution method was used [59].
Ketoconazole showed antifungal potential at MIC 0.2-1.0 mg/mL and MFC 0.3-1.5 mg/mL, respectively, while bifonazole exhibited MIC at 0.1-0.2 and MFC at 0.2-0.25 mg/mL, respectively. Compounds 8 and 9 exhibited excellent activity, with MIC/MFC at 0.08/0.11 mg/mL, respectively, against T. viride, almost fourfold better than bifonazole and 29 times better than ketoconazole, as well as against A. niger, A. versicolor, P. funiculosum, and P. cyclpoium var. verucosum, with MIC/MFC at 0.11/0.23 mg/mL, respectievly. Good activity against T. viride, with MIC and MFC at 0.11 mg/mL and 0.23 mg/mL, respectively, was also displayed by compounds 1 and 3, as well as by compounds 2, 5, and 6, with MIC/MFC at 0.17/0.23 mg/mL, respectively. Compounds 3, 5, and 8 showed the same good activity against A. niger, with compound 8 also being potent against P. cyclpoium var. verucosum. It was observed that almost all compounds displayed better activity than ketoconazole against T. viride, with the exception of compounds 4 and 7. In general, most of the compounds appeared to be more potent than ketoconazole against all fungi, except of P.v.c., against which only three compounds (1, 8, and 9) were more active than ketoconazole. The study of the structure-activity relationship revealed that the presence of 14-methyl-7,8,13b,14-tetrahydroindolo[2 ,3 :3,4]pyrido[2,1-b]quinazolin-5(13H)-one as the substituent for compound (8), connected to position 2 of the thiazole ring via N-propylpropionamide, is beneficial for antifungal activity. The replacement for this substituent with the presence of 2-methylisoquinolin-1(2H)-one led to compound (1), with decreased activity. For the series of compounds (1, 2, and 8), the presence of 2-methylisoquinolin-1(2H)-one (2) was negative for antifungal activity. In the case of the substituted phthalazine-1-yl)amino)-N-(thiazol-2yl)benzenesulfonamides, the most favorable structure for antifungal activity is the presence of a 4-chlorophenyl substituent in position 4 of the phtalazin ring in compound (5). Removal of 4-Cl-pnenyl substituent led to compound (4) having reduced activity. The least potent among all the compounds tested appeared to be compounds 6 and 7, with methylphtalazine and 4-OMe phenylphtalazine substituents decreasing activity even more. The presence of 4-Me as well as 4-OMe-Ph substituents appeared to be detrimental to antifungal activity.
As a conclusion, the antifungal activity depends upon the substituents on the thiazole ring and, in the case of phthalazin-1-yl)amino)-N-(thiazol-2-yl)benzenesulfonamides, upon the substituents on the phtalazine ring. It should be mentioned that the antifungal activity of the synthesized compounds is much better than that of the antibacterial compounds.

Docking to Antibacterial Targets
In order to predict the possible mechanism of the activity of the tested compounds, docking studies were carried out on different targets. It is widely known that the most common mechanisms of activity of antibacterial agents are destroying the integrity of cell walls and cell membranes, inhibiting the expression of proteins, inhibiting the synthesis of nucleic acids, and affecting the energy metabolism of bacteria. In this direction, for the docking studies we used the enzymes responsible for these pathways, such as E. coli DNA gyrase, thymidylate kinase, E. coli primase, and E. coli MurA and E. coli MurB enzymes.
Analyzing the docking studies scores, a low Free Energy of Binding represents a strong binding of a ligand to the enzyme. Taking this into account, the docking studies revealed that the Free Energy of Binding of all tested compounds to E. coli DNA gyrase, thymidylate kinase, and E. coli primase and E. coli MurA enzymes was higher than that of E. coli MurB (−7.02-−9.96 kcal/mol); therefore, it may be suggested that inhibition of E. coli MurB is probably the most suitable mechanism of action of the compounds where binding scores were consistent with biological activity (Table 4). The docking pose of the most active compound 3 in E. coli MurB enzyme showed two favorable hydrogen bond interactions. The first one was between the oxygen atom of -OH group of the compound and the hydrogen of the side chain of Gly47 (distance 2.25 Å), and the other hydrogen bond interaction was between the oxygen atom of the -OCH 3 group of the compound and Ser229 residue (distance 2.73 Å). The NH 2 group interacts with positive ionizable interaction with the residue Glu325, stabilizing the complex compound-enzyme and playing a vital role proving the high inhibitory action of compound 3. Moreover, the hydrogen bond formation with the residue Ser229 is crucial for the inhibitory action of compound 3 as well as for compounds 2, 4, 8, and 9, because this residue takes part in the proton transfer at the second stage of peptidoglycan synthesis [60] (Figures 2 and 3).

Docking to Antifungal Targets
All the synthesized compounds and the reference drug ketoconazole were docked to lanosterol 14α-demethylase of C. albicans and DNA topoisomerase IV (Table 5). The second-most-active compound, compound 2, also forms this hydrogen bond interaction with the residue Ser229, which explains its high inhibitory action (Figure 3). Detailed analysis of the docking pose of the two most active compounds showed that they bind MurB in a similar way as FAD, and they fit into the binding center of the enzyme, forming a hydrogen bond with the residue Ser229 (Figure 4).

Docking to Antifungal Targets
All the synthesized compounds and the reference drug ketoconazole were d lanosterol 14α-demethylase of C. albicans and DNA topoisomerase IV (Table 5).

Docking to Antifungal Targets
All the synthesized compounds and the reference drug ketoconazole were docked to lanosterol 14α-demethylase of C. albicans and DNA topoisomerase IV (Table 5). Docking results showed that the most active compound 9 binds the enzyme alongside the heme group, interacting with heme throughout its benzene ring, which forms aromatic and hydrophobic interactions. In addition, a hydrogen bond with Tyr132 residue and an -OH group of the compound are formed. Moreover, hydrophobic interactions between Ile304, ile131, Ile379, Ty188, Phe233, Phe380, Leu376, and Met508 and the compound were detected. Interaction with the heme group was also observed with the benzene ring of ketoconazole, which also forms aromatic interactions (Figures 5 and 6). This property may account for why compound 9 has good antifungal activity. Superposition of compounds 9 and 1 and ketoconazole in the lanosterol 14α-demethylase of C. albicans (CYP51 ca ) shows this interaction with the heme group proving this hypothesis (Figure 7). Docking results showed that the most active compound 9 binds the enzyme alongside the heme group, interacting with heme throughout its benzene ring, which forms aromatic and hydrophobic interactions. In addition, a hydrogen bond with Tyr132 residue and an -OH group of the compound are formed. Moreover, hydrophobic interactions between Ile304, ile131, Ile379, Ty188, Phe233, Phe380, Leu376, and Met508 and the compound were detected. Interaction with the heme group was also observed with the benzene ring of ketoconazole, which also forms aromatic interactions (Figures 5  and 6). This property may account for why compound 9 has good antifungal activity. Superposition of compounds 9 and 1 and ketoconazole in the lanosterol 14α-demethylase of C. albicans (CYP51ca) shows this interaction with the heme group proving this hypothesis (Figure 7).

Drug-Likeness
The bioavailability and drug-likeness scores of all compounds are shown in Table 6; according to prediction results, the bioavailability score of all compounds was about 0.55. Moreover, all compounds displayed good to excellent drug-likeness scores (−0.13-1.09). Figure 8 presents the bioavailability radar of some of the compounds. The best in the in silico predictions results was achieved for compounds 1 and 2, with drug-likeness scores of 1.03 and 1.09, respectively, and with no violation of any rule.

Drug-Likeness
The bioavailability and drug-likeness scores of all compounds are shown in Table 6; according to prediction results, the bioavailability score of all compounds was about 0.55. Moreover, all compounds displayed good to excellent drug-likeness scores (−0.13-1.09). Figure 8 presents the bioavailability radar of some of the compounds. The best in the in silico predictions results was achieved for compounds 1 and 2, with drug-likeness scores of 1.03 and 1.09, respectively, and with no violation of any rule. Figure 7. Superposition of compounds 9 (green), 1 (red), and ketoconazole (magenta) in lanosterol 14α-demethylase of C. albicans (CYP51 ca ). Heme group is illustrated in blue.

Drug-Likeness
The bioavailability and drug-likeness scores of all compounds are shown in Table 6; according to prediction results, the bioavailability score of all compounds was about 0.55. Moreover, all compounds displayed good to excellent drug-likeness scores (−0.13-1.09). Figure 8 presents the bioavailability radar of some of the compounds. The best in the in silico predictions results was achieved for compounds 1 and 2, with drug-likeness scores of 1.03 and 1.09, respectively, and with no violation of any rule.

General Information
1 H NMR spectra of newly synthesized compounds were recorded on a spectrometer Bruker 400 (400 MHz); compound 6-on spectrometer Bruker Fourier 300 (300 MHz) in DMSO-d 6 . Chemical shifts of nuclei 1 H were measured relatively the residual signals of deuteron solvent (δ = 2.50 ppm; see Ref. (http://chem.ch.huji.ac.il/nmr/software/solvent. htmL (accessed on 1 August 2022)) and the literature cited therein). Coupling constants (J) are reported in Hz. Melting points were determined by using Fisher-Johns Melting Point Apparatus (Fisher Scientific) and are uncorrected. Elemental analysis was performed by the classical method of microanalysis. The reaction and purity of the obtained compounds were monitored by TLC (plates with Al 2 O 3 III activity grade, eluent CHCl 3 , and development of TLC plates by exposition to iodine vapors in "iodine chamber"). The solvents were purified according to standard procedures. The starting compounds and compound 9 were provided by InterBioscreen Ltd. (Russia).

General Procedure for the Synthesis of Compounds 1, 2, and 8
A mixture of a corresponding acid (0.01 mol), SOCl 2 (1.43 g, 0.87 mL, 0.012 mol), CHCl 3 (20 mL), and DMF (0.05 mL) was refluxed until gas evolution stops and cooled, and the resulting solution of acid chloride was added dropwise at 0-2 • C to a solution of 2-(4isopropylthiazol-2-yl)ethan-1-amine (1.7 g, 0.01 mol) and Et 3 N (2.02 g, 2.78 mL, 0.02 mol) in CHCl 3 (15 mL). Then, NaHCO 3 (9.5 g) and water (100 mL) were added and stirred, the organic layer was separated and dried with Na 2 SO 4 , and the solvent was distilled off in vacuum at 30-40 • C. The residue was purified by recrystallization from a suitable solvent.

Inhibition of Biofilm Formation
The assays were performed as described before [66,67]. Briefly, P. aeruginosa resistant strain was incubated with MIC and subMIC of the tested compounds in tryptic soy broth enriched with 2% glucose at 37 • C for 24 h. Afterwards, each well was washed twice with sterile Phosphate buffered saline, pH 7.4 (PBS), and fixed with methanol for 10 min. Methanol was then removed, and the plate was air-dried. The biofilm was stained with 0.1% crystal violet (Bio-Merieux, France) for 30 min. The wells were washed with water, airdried, and color dissolved in 96% ethanol (Zorka, Serbia). The absorbance was measured at 620 nm on a Multiskan FC Microplate Photometer, Thermo Scientific. The percentage of inhibition of biofilm formation was calculated by the formula: [(A620control − A620sample)/A620control] × 100. (1)

Molecular Modeling Studies
The ligand preparation done by using chemdraw12.0, and geometries were optimized using LigandScout 4.4.5. The "Build/check/repair model" for the session "Prepare PDB file for docking programs" module was used for proteins preparation. For the final preparation of both ligands and protein preparation, Wizard of AutoDock tools 1.5.6 is used. Autodock 4 (ver. 4.2.6) was employed for docking simulations and Autogrid4 for affinity grid maps preparation. The resulting poses and potential interactions were visualized using LigandScout 4.4.5.
X-ray crystal structures of E. coli DNA GyrB, thymidylate kinase, E. coli MurA, E. coli primase, E. coli MurB, DNA topoisomerase IV, and CYP51 of C. albicans (PDB ID: 1KZN, AQGG, 1DDE, JV4T, 2Q85, 1S16, and 5V5Z, respectively) with bound inhibitors were retrieved from Brookhaven Protein Data Bank (PDB). The pdb files of proteins were submitted to "Build/check/repair model" for the session "Prepare PDB file for docking programs"; missing side chains were modeled in, water positions and symmetry were corrected, and hydrogen atoms were added. Only chain A of each enzyme of the repaired pdb file was evaluated and passed to AutodockTools (ADT ver.1.5.6) for PDBQT file preparation. ADT assigned polar hydrogens, water molecules and nonstandard residues were removed, so only polar hydrogen was maintained, and Gasteiger charges were computed for protein atoms. AutoDock saved the prepared file in PDBQT format.
All molecules were sketched in Chemdraw12.0 program. The geometry of built compounds was optimized using the molecular mechanical force fields 94 (MMFF94) energy via LigandScout [68], partial charges were also calculated, comformers of each ligand were generated, and the one with the best conformation was maintained and saved as mol2 file that was passed, as usual, to ADT for PDBQT file preparation. There, polar hydrogen was added to each structure, followed by computing Gasteiger and Kollman charges and the torsions.
Autodock 4 (ver. 4.2.6) was employed for docking simulations. A computationally (relatively) 'hybrid' force field that contains terms based on molecular, mechanics, and empirical terms is used by AutoDock. The evaluation step includes: First, calculation of the energy of protein and ligand in the unbound state. Second, calculation of the energy of the ligand-protein complex. Third, taking the difference between first and second steps.
where P refers to the protein, L refers to the ligand, V are the pair-wise evaluations mentioned above, and ∆S conf denotes the loss of conformational entropy upon binding [69]. The ligand molecule is in an arbitrary conformation, orientation, and position, and this molecular docking program finds favorable poses in a protein-binding site using Lamarckian genetic algorithms implemented therein to search for the best conformers. A Lamarckian genetic algorithm was used as the search engine, with a total of 100 runs. The region of interest, used by Autodock4 for docking runs and by Autogrid4 for affinity grid maps preparation, was defined in such a way to comprise the whole catalytic binding site using a grid of 50 × 50 × 50 points with a grid space of 0.375 Å. All parameters used in docking were default. The translation, quaternion, and torsions steps were taken from default values in AutoDock. The Lamarckian genetic algorithm and the pseudo-Solis and Wets methods were applied for minimization using default parameters. The number of docking runs was 100. After docking, the 100 solutions were clustered into groups, with RMS lower than 1.0 E. The clusters were ranked by the lowest energy representative of each cluster. Upon completion of docking, the best poses were screened by examination of binding energy (∆G binding , kcal/mol) and number in cluster. In order to describe the ligand-binding pocket interactions, the top-ranked binding mode found by AutoDock in complex with the binding pocket of enzyme was selected. The resulting poses and potential interactions were visualized using LigandScout.

Conclusions
In this work, three structural series of new thiazole derivatives were synthesized and evaluated for their antibacterial and antifungal activity against a series of bacterial and fungal pathogens. The antibacterial activity of the tested compounds is moderate to good, with MIC at 0.23->3.75 mg/mL and MBC at 0.35->3.75 mg/mL. Compounds 4 and 9 demonstrated the best activity among the tested compounds against E. coli and B. cereus and S.Typhimurium, respectively, with MIC/MBC at 0.17/0.23 mg/mL, respectively.
Three of the most active compounds (2, 3, and 4) were also evaluated against three resistant strains, MRSA, E. coli, and P. artuginosa, demonstrating better activity than the reference drugs against MRSA, while compound 4 also was active against P. aeruginosa.
According to the results on antifungal activity, all compounds are active, but the best activity was observed for compound 8, with MIC and MFC in the range of 0.08-0.23 and 0.11-0.47 mg/mL, respectively.
Docking analysis indicated a probable involvement of MurB inhibition in the antibacterial mechanism of the compounds tested, while the docking analysis to 14α-lanosterol demethylase (CYP51) of Candida albicans indicated a probable implication of CYP51 reductase at the antifungal activity of the compounds. Finally, compound 8 showed the best drug-likeness model score.