Pathak Prateek, Novak Jurica, Shukla Parjanya K, Grishina Maria, Potemkin Vladimir, Verma Amita
Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.
Krishnarpit Institute of Pharmacy, Dr. A. P. J. Abdul Kalam Technical University, Prayagraj, Uttar Pradesh, India.
Arch Pharm (Weinheim). 2021 Jun;354(6):e2000473. doi: 10.1002/ardp.202000473. Epub 2021 Mar 3.
Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine-1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods ( H and C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure-activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
由于目前使用的抗生素出现耐药性，细菌感染对人类健康构成严重威胁。随着新型抗生素种类的短缺，抗生素耐药性不断增加和广泛传播的问题日益严重，在严重细菌感染的治疗方面产生了大量未满足的医疗需求。因此，在本研究中，我们报告了18种新型噻唑烷-1,2,4-三唑杂化衍生物作为DNA促旋酶抑制剂。这些衍生物通过多步有机合成法制备，并通过光谱方法（氢和碳核磁共振以及质谱）进行表征。对这些衍生物进行了DNA促旋酶抑制测试，结果表明合成的衍生物具有抑制DNA促旋酶功能的趋势。此外，还测试了这些化合物对三种革兰氏阳性菌（枯草芽孢杆菌[NCIM 2063]、蜡样芽孢杆菌[NCIM 2156]、金黄色葡萄球菌[NCIM 2079]）和两种革兰氏阴性菌（大肠杆菌[NCIM 2065]、普通变形杆菌[NCIM 2027]）的抗菌活性。这些衍生物表现出显著至中等程度的抗菌活性以及明显的抗生物膜效果。还进行了定量构效关系（QSAR）、ADME（吸收、分布、代谢、排泄）计算、分子对接、径向分布函数和二维指纹图谱分析，以阐明其生物活性所必需 的基本结构片段。这些研究表明，衍生物10b和10n具有潜在的抗菌特性以及显著的DNA促旋酶抑制效果，它们可作为进一步开发新型广谱抗菌剂的起始骨架。
