Abstract

Multidrug resistance mechanism of microorganisms towards conventional antimicrobials nowadays faces a common health problem. So, searching and development of new antibacterials are in the frontier areas of biochemistry. Functionalizations of various natural products or synthesis of compounds through molecular modeling followed by virtual screening are the ways to obtain potential leads. Chrysin is one of the plant secondary metabolites and is ubiquitously present in majority of plants. It has multi-dimensional potentiality however, with a very low bioavailability causing a very low efficacy. Very few chrysin derivatives possessing antimicrobial activity with a low anti-biofilm efficacy have been found in the literature. Thus, it has been attempted to synthesize a series of new chrysin derivatives (CDs). In this study, twenty-two new derivatives have been synthesized via its 7-OH modulation and antibiofilm activity was evaluated against a model bacterium viz. Escherichia coli MTCC 40 (Gram negative). Eleven CDs coded as 2a, 2b, 2c, 2e, 2f, 2g, 2h, 2i, 3j, 3k and 3l have been found more potent compared to chrysin (precursor of CDs) against planktonic form of E. coli. Biofilm inhibition studies indicated a noteworthy results for 2a (93.57%), 2b (92.14%), 2f (92.14%) and 3l (93.57%) compared to chrysin (33.57%). E. coli motility was also highly restricted by 2a, 2b, 2f and 3l than chrysin at their sub-inhibitory concentrations. Solubility studies indicated an extended-release of 2a, 2b, 2f and 3l in physiological systems. Relatively higher bioavailability of 2a, 2b, 2f and 3l than chrysin was revealed from the dissolution experiments and was further validated through in silico ADME-based SAR analysis. Hence, this study is more interesting in regard to antibacterial potentiality of chrysin derivatives against Escherichia coli MTCC 40 (Gram negative). Thus, this article might be useful for further design and development of new leads in the context of biofilm-associated bacterial infections.

Graphic abstract

中文翻译：

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具有显着抗生物膜活性的新白杨素衍生物的合成

摘要

微生物对常规抗菌药物的多药耐药机制是当今面临的一个共同的健康问题。因此，寻找和开发新型抗菌药物处于生物化学的前沿领域。通过分子建模和虚拟筛选对各种天然产物进行功能化或合成化合物是获得潜在线索的方法。白杨素是植物次生代谢产物之一，普遍存在于大多数植物中。然而，它具有多维潜力，具有非常低的生物利用度，导致非常低的功效。在文献中很少发现具有抗生物膜功效的抗微生物活性的白杨素衍生物。因此，已尝试合成一系列新的白杨素衍生物（CDs）。在这项研究中，. 大肠杆菌MTCC 40（革兰氏阴性）。已发现与白杨素（CD 的前体）相比，编码为2a、2b、2c、2e、2f、2g、2h、2i、3j、3k和3l的 11 种 CD 对浮游形式的大肠杆菌更有效。生物膜抑制研究表明，与白杨素 (33.57%) 相比， 2a (93.57%)、2b (92.14%)、2f (92.14%) 和3l (93.57%)的结果值得注意。大肠杆菌在亚抑制浓度下，与白杨素相比， 2a、2b、2f和3l的运动性也受到高度限制。溶解度研究表明2a、2b、2f和3l在生理系统中的缓释。溶出实验表明2a、2b、2f和3l的生物利用度高于白杨素，并通过基于计算机 ADME 的 SAR 分析进一步验证。因此，这项研究更有趣的是白杨素衍生物对大肠杆菌的抗菌潜力MTCC 40（革兰氏阴性）。因此，本文可能有助于在生物膜相关细菌感染的背景下进一步设计和开发新的线索。

图形摘要