Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity

Abstract

Azetidin-2-one analogues are reported to exhibit various pharmacological activities like cholesterol absorption inhibitory activity, human tryptase, thrombin and chymase inhibitory activity, vasopressin V1a antagonist activity, antidiabetic, anti-inflammatory, antiparkinsonian and anti-HIV activity in addition to antimicrobial. 1-6 In the present study, Isoniazid (INH), the established antitubercular drug was selected as the lead for the design and development of antitubercular agents with minimal toxic effects. A novel series of amino azetidinones were designed from corresponding azetidin-2-ones using various in silico methods. Docking studies were performed at Mtb enoyl acp reductase (4DRE) and the derivatives exhibited best docking scores were prepared from corresponding azetidin-2-ones by treating with various molecules containing amino groups in the presence of TEA. Azetidin-2-ones in turn were obtained from a series of INH Schiff bases by reaction with chloro acetyl chloride. Structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, 1 H NMR, 13 CNMR and mass spectral studies. The newly synthesized compounds were screened for their in vitro antitubercular activity using Alamar blue assay method and the hepatotoxicity was determined by MTT assay method using chang liver cells. AAZ1V, the amino azetidinone obtained from N-[3-chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-yl] pyridine-4-carboxamide (AZ1V) by combining with 4-amino 1, 2, 4-triazole produced significant antitubercular activity. The percentage viability produced by AAZ1V against Chang liver cells for hepatotoxicity was better than the percentage viability produced by INH.

Synthesis, Molecular Modeling, and Quantitative Structure–activity Relationship Studies of Undec-10-Enehydrazide Derivatives as Antimicrobial Agents

“…corresponding hydrazide derivatives (17)(18)(19). The physicochemical characteristics of synthesized compounds are presented in Table 1.…”

“…The synthesis of the intermediate (2,3) and target compounds (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) was performed according to reactions outlined in Schemes 1 and 2. A methanolic solution of undecylenic acid 1 was refluxed in the presence of sulfuric acid to yield the methyl ester undecylenic acid (2).…”

“…Studies reported by various research groups also showed that hydrazide-hydrazone derivatives of different acids have wide range of biological activities, viz., antibacterial [12], antifungal [13], antitubercular [14], trypnocidal [15], antimalarial [16], antiviral [8], anti-inflammatory [17], and antitumor [18] activities. Isoniazid (antitubercular) [19], nifuroxazide (antidiarrheal and antitumor) [20], nifurtimox (antiamoebic) [21], furacin (antibiotic) [22], and furazolidone (antibacterial) [23] are hydrazide containing important biologically active drug molecules. Moreover, SAR studies indicated that substitution at a specific position in aromatic ring attached to hydrazide moiety and conversion of hydrazide moiety to hydrazone/pyrazole/oxadiazole/4-oxoazitidine based molecules affect the biological activity to a great extent [9,24,25].…”

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“…Compounds, (E)-N' -(3-formylbenzylidene) isonicotinohydrazide (38), (E) -N' -(4-formylbenzylidene) isonicotino hydrazide (39), (E)-N'-(4-(hydroxymethyl) benzyli dene) isonicotinohydrazide (40), N'-cyclo penty lideneisonicotinohydrazide (41) and N'-(4-phenylcyclohexylidene) isonicotinohydrazide (42) showed measured activities against H37Rv higher than INH (i.e., MIC < 0.28 mM) 72 . Pyrazinamide as Target: The pyrazine nucleus is an important heteroaromatic class of compounds with a wide range of pharmacological activities such as antibacterial, anti-inflammatory, anticancer, anti-diabetic, and sedative 74 .…”

Structural and spectroscopic characterization oF N’-[(1E)-(4-fluorophenyl)methylidene]thiophene-2-carbohydrazide, a potential precursor to bioactive agents

“…As a result of an extensive search based on homocyclic and heterocyclic hydrazides and hydrazones, several derivatives were developed and proved to be superior to INH [2][3][4][5][6][7][8]. In addition, several hydrazide and hydrazine derivatives were reported to possess marked antifungal [9][10][11][12], antileishmanial [13,14], antiviral [15], anticancer [16][17][18], anti-inflammatory [19] and antioxidant [20] activities.…”