Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N’-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-29 DOI:10.1002/cmdc.202500085
Priam-Amedeo Houngbedji, Daria Elżbieta Nawrot, Ondřej Janďourek, Klára Konečná, Martin Novák, Pavla Paterová, Pavel Bárta, Martina Hrast Rambaher, Eva Novotná, Carlo Castellano, Matteo Mori, Fiorella Meneghetti, Monika Záhorszká, Jana Korduláková, Jan Zitko
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Abstract

A series of 33 (E)-N’-benzylidenepyrazine-2-carbohydrazides and their derivatives were synthesized and tested for biological activity. Benzylidene derivatives with 2-OH substitution on the phenyl ring (18: R = 2-OH, 21: R = 2,3-diOH, and 22: R = 2,4-diOH) exhibit various biological activities. Compounds 18 and 21 demonstrate antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. tuberculosis H37Rv, and M. aurum, with minimum inhibitory concentration values ranging from 15.625 to 62.5 μg mL−1. Compounds 18, 21, and 22 show mild cytotoxicity on several human cell lines (IC50 ranging from 70.2 to 500 μM). Crystallographic studies confirm the (E)-configuration of compound 18 and a nearly planar molecular conformation. Due to their structural similarity with salicylaldehyde isonicotinoyl hydrazone (SIH), a known iron chelator, selected compounds were tested for iron-chelating properties, revealing comparable or superior activity. Mechanistic assays targeting enoyl-[acyl carrier protein] reductase (InhA), isocitrate lyase (ICL), and lipid/mycolic acid biosynthesis show no significant inhibition, suggesting a nonspecific mechanism potentially linked to iron chelation. A correlation is observed between chelating activity and cytotoxicity, while antimycobacterial activity appears to involve additional mechanisms. Pharmacokinetic studies with compound 18 reveal no specific plasma metabolites, and no significant metabolites are detected after incubation with human liver microsomes.

Abstract Image

(E)-N′-苄基哌嗪-2-碳酰肼及其衍生物的抑菌和抗增殖作用机制研究。
合成了一系列33 (E)-N′-苄基哌嗪-2-碳肼及其衍生物,并对其生物活性进行了测试。苯基环上2- oh取代的苄基衍生物(18:R = 2- oh, 21: R = 2,3- dioh和22:R = 2,4- dioh)表现出不同的生物活性。化合物18和21对结核分枝杆菌H37Ra、结核分枝杆菌H37Rv和金黄色分枝杆菌具有较强的抑菌活性,最小抑菌浓度在15.625 ~ 62.5 μg mL-1之间。化合物18、21和22对多种人类细胞系表现出轻微的细胞毒性(IC50范围为70.2 ~ 500 μM)。晶体学研究证实了化合物18的(E)构型和接近平面的分子构象。由于它们与已知的铁螯合剂水杨醛异烟碱酰腙(SIH)的结构相似,对所选化合物进行了铁螯合性能测试,显示出相当或更好的活性。针对烯丙基-[酰基载体蛋白]还原酶(InhA)、异柠檬酸裂解酶(ICL)和脂质/霉菌酸生物合成的机制分析显示,没有明显的抑制作用,表明可能与铁螯合作用有关的非特异性机制。观察到螯合活性和细胞毒性之间的相关性,而抗真菌活性似乎涉及其他机制。化合物18的药代动力学研究显示没有特异性血浆代谢物,与人肝微粒体孵育后也没有检测到显著代谢物。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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