Design, synthesis, and molecular docking studies of thiazole derivatives against phospholipase A₂ (Naja oxiana) venom.

IF 3.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Future medicinal chemistry Pub Date : 2025-03-01 Epub Date: 2025-03-17 DOI:10.1080/17568919.2025.2478807

Bibi F Nayyab, Muhammad Shah, Muhammad H H B Asad, Asma Zaidi, Fiaz Alam, Abdul Mannan, Umer Rashid

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引用次数: 0

Abstract

Aim: Cobra venom phospholipase A₂ (PLA₂) has been known to induce life threatening effects post-envenomation in the victims. Being the most abundant and noxious component of snake venom, present study was envisaged to investigate new drug candidates against PLA₂ enzyme.

Methods: Amide and sulfonamide thiazole derivatives were synthesized and characterized using FTIR, ¹HNMR and ¹³CNMR followed by docking targeted protein techniques. Furthermore, synthetic analogues were evaluated in vitro for their potentials to neutralize PLA₂ activity.

Results: Among the pool of synthetic derivatives, compound (7) (ethyl 2-(2-(4-isobutylphenyl)propanamido)thiazole-4-carboxylate) was found to be completely effective (p > 0.05; IC₅₀ = 1 nM) to mask cent percent PLA₂ activity. Moreover, Ramachandran plot further conferred about the location of amino acid residues in the most favored region and, therefore, attributed to confiscate PLA₂ activity. Furthermore, ADME profile suggested that compound (7) possesses systemic bioavailability and efficacy with favorable safety profile (high solubility, membrane permeability, metabolic stability, and low potential for off-target results).

Conclusion: Present study highlighted compound (7) as a potential PLA₂ inhibitor to reverse PLA₂-induced snake venom poisoning in future.

查看原文本刊更多论文

抗磷脂酶A2 （Naja oxana）毒液的噻唑衍生物的设计、合成及分子对接研究。

目的：已知眼镜蛇毒液磷脂酶A2 （PLA2）在受害者中毒后会引起危及生命的影响。PLA2酶是蛇毒中含量最丰富、毒性最强的成分，本研究旨在开发新的抗PLA2酶候选药物。方法：合成酰胺类和磺胺类噻唑衍生物，采用FTIR、1HNMR和13CNMR对其进行表征，并对接靶向蛋白技术。此外，合成类似物在体外评估其中和PLA2活性的潜力。结果：在合成的衍生物中，化合物(7)（乙基2-（2-（4-异丁基苯基）丙胺）噻唑-4-羧酸酯）是完全有效的(p < 0.05；IC50 = 1 nM)来掩盖PLA2活性的百分比。此外，Ramachandran图进一步确定了氨基酸残基在最有利区域的位置，因此归因于没收PLA2活性。此外，ADME谱表明，化合物(7)具有全身生物利用度和有效性，且具有良好的安全性（高溶解度、膜渗透性、代谢稳定性和低脱靶可能性）。结论：化合物(7)是一种潜在的PLA2抑制剂，可以逆转PLA2诱导的蛇毒中毒。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Future medicinal chemistry CHEMISTRY, MEDICINAL-

CiteScore

5.80

自引率

2.40%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.