Synthesis, Characterization, and Biologic Activity of New Acyl Hydrazides and 1,3,4-Oxadiazole Derivatives.

Irina Zarafu,Carmen Limban,Petre Ionita,Roxana Maria Nemeș,Anamaria Hanganu,Ioana Nicolau,Coralia Bleotu,Anca Păun,Cristiana Radulescu,Diana Camelia Nuta,Carmen Cristina Diaconu,Arnaud Tatibouët,Lilia Matei

doi:10.3390/molecules25143308

Abstract

Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti-Mycobacterium tuberculosis effects) was proved by 9. Compounds 7, 8, and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7, 8, and 9, seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.

Highlights

Hydrazides represent a class of organic compounds containing a nitrogen–nitrogen covalent bond with at least one acyl substituent [1]
The benzoic acid hydrazides were prepared following the method described in the general experimental procedure
The crude3acid chloride obtained was added to isoniazid dissolved in dichloromethane and the reaction mixture

Summary

Introduction

Hydrazides represent a class of organic compounds containing a nitrogen–nitrogen covalent bond with at least one acyl substituent [1]. The active forms of INH shown different effects on the cell wall mycolic acids synthesis [18], on nucleic acids replication/transcription [19], and on bacterial respiratory metabolism, as well [20]. All this time, it never been completely discovered the complex mechanism of action of isoniazid as prodrug [21,22]

Methods

Results

Conclusion