Chrysin based pyrimidine-piperazine hybrids: design, synthesis, in vitro antimicrobial and in silico E. coli topoisomerase II DNA gyrase efficacy

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2023-06-15 DOI:10.1007/s11030-023-10663-1

Kajalben B. Patel, Dhanji Rajani, Iqrar Ahmad, Harun Patel, Hitesh D. Patel, Premlata Kumari

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Abstract

Ten chrysin-based pyrimidine-piperazine hybrids have been evaluated in vitro for antimicrobial activity against eleven bacterial and two fungal strains. All compounds 5a–j exhibited moderate to good inhibition, with MIC values ranging from 6.25 to 250 µg/ml. At 6.25 µg/ml and 12.5 µg/ml MIC values, respectively, compounds 5b and 5h demonstrated the most promising potency against E. coli, outperforming ampicillin, chloramphenicol, and ciprofloxacin. None of the substances had the same level of action as norfloxacin. 5a, 5d, 5g, 5h, and 5i have exhibited superior antifungal efficacy than Griseofulvin against C. albicans with 250 µg/ml MIC. All the compounds were also individually docked into the E. coli DNA gyrase ATP binding site (PDB ID: 1KZN) and CYP51 inhibitor (PDB ID: 5V5Z). The most active compound, 5h and 5g displayed a Glide docking score of − 5.97 kcal/mol and − 10.99 kcal/mol against DNA gyrase and 14α-demethylase enzyme CYP51 respectively. Potent compounds 5b, 5h, and 5g may be used to design new, innovative antimicrobial agents, according to in vitro, ADMET, and in silico biological efficacy analyses.

Graphical abstract

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基于金黄素的嘧啶-哌嗪杂交化合物：设计、合成、体外抗菌和硅学大肠杆菌拓扑异构酶 II DNA 回旋酶功效。

体外评估了十种基于菊黄素的嘧啶-哌嗪杂交化合物对十一种细菌和两种真菌菌株的抗菌活性。所有化合物 5a-j 都表现出中等到良好的抑制作用，MIC 值范围在 6.25 到 250 µg/ml 之间。化合物 5b 和 5h 的 MIC 值分别为 6.25 µg/ml 和 12.5 µg/ml，对大肠杆菌的抑制效果最好，优于氨苄西林、氯霉素和环丙沙星。这些物质的作用水平都不及诺氟沙星。5a、5d、5g、5h 和 5i 对白僵菌的抗真菌效果优于 MIC 值为 250 µg/ml 的格列沙芬。所有化合物还分别对接了大肠杆菌 DNA 回旋酶 ATP 结合位点（PDB ID：1KZN）和 CYP51 抑制剂（PDB ID：5V5Z）。活性最强的化合物 5h 和 5g 对 DNA 回旋酶和 14α-demethylase 酶 CYP51 的 Glide docking 得分分别为 - 5.97 kcal/mol 和 - 10.99 kcal/mol。根据体外、ADMET 和硅学生物药效分析，强效化合物 5b、5h 和 5g 可用于设计新型、创新的抗菌剂。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;