Design, Synthesis and In vitro Antitubercular Effect of New Chalcone Derivatives Coupled with 1,2,3-Triazoles: A Computational Docking Techniques.

A very interesting foundation for this study is the creation of new methods for modifying compounds with a 1,2,3-triazole and chalcone scaffolds, as these compounds are significant in organic synthesis, particularly in the synthesis of bioactive organic compounds. To contribute to the development of an efficient method for the conversion of antimicrobial and antituberculosis heterocyclics, a novel series of cyclohepta pyridinone fused 1,2,3-triazolyl chalcones were designed and synthesized. All the newly prepared scaffolds were characterized by FT-IR, NMR (1H & 13C) and mass spectrometry. Among the tested compounds, hybrids 8b, 8d, and 8f exhibited exceptional antibacterial susceptibilities with zone of inhibition 27.84±0.04, 32.27±0.02, and 38.26±0.01 mm against the tested E. faecalis bacteria, whereas 8d had better antitubercular potency against M. tuberculosis H37Rv strain with MIC value 5.25 µg/mL, compared to Streptomycin [MIC=5.01 µg/mL]. All the synthesized compounds were initially assessed in silico against the targeted protein i. e., DprE1 that indicated compound 8d, 8f and 8h along with several other 1,2,3-triazole compounds as possible inhibitors. Based on docking results, 8d showed that the amino acids His74(A), Lys76(A), Cys332(A), Asp331(A), Val307(A), Tyr357(A), Met226(A), Gln276(A), Gly75(A), Peo58(A), Leu259(A), and Lys309(A) exhibited highly stable binding to DprE1 receptor of Mycobacterium tuberculosis (PDB: 4G3 U). Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion).

Synthesis and in Silico Studies of Some New 1,2,3-Triazolyltetrazole Bearing Indazole Derivatives as Potent Antimicrobial Agents.

1,2,3-Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. Novel indazole bearing 1,2,3-triazolyltetrazoles were designed as potential antimicrobial candidates. The structure of duel heterocyclics was validated by a spectroscopic technique of infrared (IR), nuclear magnetic resonance (1 H and 13 C NMR), and mass spectral data. Compounds 4b, 4c, 4d, and 4h were found to have a stronger antibacterial effect against Gram-positive (S. aureus, B. subtilis, M. Luteus) and Gram-negative (E. coli, P. aeruginosa) microorganisms with MICs ranging from 5±0.03-18±0.02 µM, respectively. Moreover, scaffolds 4a, 4h showed potent antifungal activity against A. flavus, M. gypsuem strains with MIC values of 10±0.02, 11±0.01 µM, which are similar activity that of the standard Itraconazole (MIC=8±0.02, 10±0.01 µM). The binding mode for compound 4 inside the catalytic pocket of S. aureus complexed with nicotinamide adenine dinucleotide phosphate and trimethoprim and produced a network of hydrophobic and hydrophilic interactions (3FRE). From in silico results, 4b demonstrated highly stable hydrogen binding amino acids Leu62(X) [N18…O, 2.47 Å], Arg44(X) [N17…N, 3.11 Å], Thr96(X) [N10…OG1, 3.05 Å], Gly94(X) [F7…N, 2.82 Å], and Gly43(X) [F7…N, 2.90 Å], which are plays a crucial role in ensuring efficient binding of the ligand in a crystal structure of antibacterial receptor. Furthermore, the physicochemical and ADME filtration molecular properties, estimation of toxicity, and bioactivity scores of these novel scaffolds were evaluated by using SwissADME and ADMETlab2.0 online protocols. Thus, the significant antimicrobial activity of indazole linked to duel heterocyclic compounds can be used for development of new antimicrobial agents with further modifications.

New Fluoroquinolone-1,2,4-triazoles as Potent Antibacterial Agents: Design, Synthesis, Docking Studies and in Silico ADME Profiles.

Our current work is aimed at synthesizing novel substituted 1,2,4-triazolyl-fluoroquinolone analogs and study of their biological activity to find active promising molecules. The structural elucidation of the products was demonstrated by a variety of spectroscopic methods such as IR, 1 H-NMR, 13 C-NMR, mass and elemental analysis. The newly synthesized 1,2,4-triazole derivatives were tested in vitro for their ability to inhibit the growth of seven different microbes including S. epidermidis, S. pneumoniae, S. aureus, B. subtilis, K. pneumoniae, E. coli, and P. aeruginosa. Five FQ derivatives 5d, 5e, 5h, 5j, and 5b have demonstrated good antibacterial activity against S. pneumoniae with MICs ranging from 2.5-22.0 µg/mL, while 5c, 5g reported comparable activity against P. aeruginosa with respect to the standard drugs moxifloxacin and ciprofloxacin. The possible mechanism of antibacterial activity of fluoroquinolones was investigated via molecular docking by using DNA gyrase of S. pneumoniae (3RAE). The pefloxacin derivatives also tended a good antibacterial ability based on the results of the molecular docking, ligand 5h with good binding affinity (-9.92 Kcal/mol) and binding site interactions via ValA:86, SerA:79, TyrA:82, MetA:116, AspA:78, AlaA:63, ArgA:117, ProA:112, ProA:113, AlaA:115, AlaA:114. These scaffolds were further evaluated for their ADMET and physicochemical properties by using SwissADME, ADMETlab2.0 web server as a good oral bioavailability.

Design, Synthesis and Bio-Evaluation of Novel Chalcones Bridged with 1,3,4-Oxadiazole Linkers: ADMET and Docking Analysis.

In this article, we prepared a novel series of 1,3,4-oxadiazoles containing chalcone analogs via replacement of phthalazine which had increased antibacterial activity and the final compounds were confirmed by proton, carbon nuclear magnetic resonance spectroscopy, infrared and mass spectral analysis. Two sets of 1,3,4-oxadiazoles like 2-methyl-5-substitutedbenzylthio-1,3,4-oxadiazolyl-4-methylphthalazine-2-ones (3a-f), (E)-substituted phenyl acryloylphenyl-4-methyl-1-oxophthalazine-1,3,4-oxadiazolylthioacetamides (5a-f) were designed, synthesized and evaluated for their in vitro antibacterial potency against different Gram-(+ve), Gram-(-ve) microorganisms and fungal strains. The synthesized 4-methyl-2-{[5-({[2-(trifluoromethyl)phenyl]methyl}sulfanyl)-1,3,4-oxadiazol-2-yl]methyl}phthalazin-1(2H)-one (3c), 4-methyl-2-[(5-{[(4-nitrophenyl)methyl]sulfanyl}-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2H)-one (3d), N-(4-{(2E)-3-[2-(dimethylamino)phenyl]prop-2-enoyl}phenyl)-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5d), and N-{4-[(2E)-3-(3-hydroxy-4-methoxyphenyl)prop-2-enoyl]phenyl}-2-({5-[(4-methyl-1-oxophthalazin-2(1H)-yl)methyl]-1,3,4-oxadiazol-2-yl}sulfanyl)acetamide (5e) displayed improved activity with MICs 1.41, 0.87, 2.16, 0.89 µg/mL as compared to the standard drugs rifamycin, ciprofloxacin, fluconazole (MIC=1.52, 1.94, 3.02 µg/mL). The prepared compounds were also analyzed with better target binding towards bacterial bioavailability, 5e exhibited highest bonds with amino acids ArgA45 , LysA20 , LysA17 , ArgA171 , AspA49 , IleA14 , HisA18 and having docking energy -8.68 Kcal/mol and dissociation constant 432.48 nM, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.