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 1,3,4‒oxadiazole Quinazolines as Potential Anticancer Agents: Design, Synthesis, Biological Evaluation, and In silico Studies.

BACKGROUND: A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and Topoisomerase‒ II inhibitory activity was evaluated. OBJECTIVE: These findings inspired the design, synthesis, and biological analysis of these 1,3,4‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors. METHODS: The novel compound structures were determined using mass spectrometry and spectral methods (IR, NMR: 1H & 13C). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs, and Autodock 4.2 provides a description of the docking results. For the more active members, additional biological tests, such as the Topo‒II inhibition experiment, were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail. RESULTS: In the experiment for antiproliferative activity, compounds 7d, 7e, 8c, 8e, and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines, with IC50 values ranging from 3.85 to 19.43 µM. Compounds 7d, 7e, and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18, 17.55, and 12.59 µM, respectively. Additionally, the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B), Asn508(B), Asn520(B), and Glu522(B) in the Human topoisomerase‒IIß active site in the DNA complex (4G0U) when compared to the findings of docking experiments. CONCLUSIONS: New findings have discovered the fact that fused 1,3,4‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally, the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME, where some of the compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure, a potent anticancer agent can be generated with good efficacy.