Synthesis, characterization and biological evaluation of few hydroxamic acid derivatives

Abstract

A series of 5-substituted-4-amino-1, 2, 4-triazole linked hydroxamic acid derivatives have been synthesized and explored in vitro to evaluate antibacterial and antifungal activities. Different 5-Phenyl group substituted-4-amino-1,2,4-triazole-3-thiol reacted with chlorine substituted hydroxamic acid to produce the desired compounds and characterized spectroscopically. Minimum inhibitory concentration (MIC), zone of inhibition (ZOI), growth kinetic studies and scanning electron microscopy (SEM) were employed to elicit the antimicrobial efficacy of synthesized compounds against wide range of bacterial and fungal strains. To evaluate in vitro antioxidant activity, DPPH assay, ABTS assay and total antioxidant capacity assay were carried out. IC50 values were calculated against MDA-MB-231, MCF-7 and HCT 116 cell lines and in vivo anticancer potential was evaluated against EAC induced mice model. Different biological markers were examined for drug related toxicities. Antileishmanial efficacy was evaluated by the determination of selectivity index (SI) against Leishmania donovani AG83 wild type, field type and drug resistant amastigotes. Compounds 6a, 6b, 6d, 6k (MIC of 25μg/ml) have been found to be more potent against Klebsiella pneumoniae, Bacillus cereus, Bacillus pumilus, Micrococcus luteus and Pseudomonas aeruginosa, compound 6a- 6d, 6k, 6l (MIC of 25-50μg/ml) have shown potent antibacterial efficacy against Klebsiella pneumonia, Pseudomonas aeruginosa and Vibrio cholera compare to the standard drug amoxicillin (MIC of 60μg/ml, 65μg/ml and 25μg/ml respectively). Screening for the antifungal activity revealed that the compounds were found to be most active against Candida albicans (6a, 6b, 6l); Candida tropicalis (6b, 6d) and Aspergillus niger (6a, 6b, 6d, 6j) with MIC of 15-25μg/ml. Bacteriostatic and fungistatic effect of titled compounds were reveled from growth kinetics study. Compound 6b revealed more potent antioxidant property among all tested compounds, even than the ascorbic acid. The IC50 values of compound 6b were found to be 5.71 ± 2.29 μg/ml (DPPH assay) and 4.12 ± 0.5 μg/ml (ABTS assay). Histopathology of liver sections of drug treated mice was evaluated. As the elevated life span of diseased animals is a decisive factor to assess the value of any anticancer agent, percent survival analysis was performed. Among all the synthesized compounds, compound 6e have higher SI values against AG83 wild type (99.38), SSG-R (81.09), PMM-R (91.10) and GE1 field type (83.39) strains followed by compound 6f even compare to the SI values of amphotericin B for respective strains. According to SI index, the synthesized compounds were oriented in a descending manner as per the antileishmanial efficacy like, Wild type: 6e> 6f> 6c> 6k> 6d> 6l> 6g> 6h> 6j> 6i> 6a> 6b SSG-R: 6e> 6f> 6d> 6c> 6k> 6l> 6h> 6g> 6j> 6i> 6a> 6b PMM-R: 6e> 6f> 6d> 6c> 6k> 6l> 6h> 6g> 6j> 6i> 6a> 6b GE1: 6e> 6c> 6f> 6d> 6k> 6l> 6g> 6h> 6j> 6i> 6a> 6b A series of twelve 5-substituted-1,2,4-triazole linked hydroxamic acid derivatives (6a-6l) were synthesized and evaluated for their in vitro antimicrobial, antioxidant, antileishmanial and anticancer (both in vivo and in vitro) efficacy. The significant antimicrobial property may be attributed to the putative substructure of triazole (which itself can form ionic interaction with various microbial target; the most acceptable is lanosterol-14α-demethylase in Candida albicans) and the salient feature of hydroxamic group. The aryl group with its substituent leaves a mixed opinion with respect to the biological interaction. The electron donating ability of methyl, mercapto, amino group strengthen the binding affinity of the aryl group with the active site of the target might be one of strong supporting evidence for their potency. It could be concluded that compound 6b has shown potent antioxidant activity among all other tested compounds. Though other tested compounds have shown moderate to low antioxidant activity compared to the standard, ascorbic acid. It could be suggested from the fact that pyridyl substitution at R1 position was important to exert superior antioxidant properties. After the assessment of all in vivo anticancer study related data it was found that compound 6b possess superior anticancer potency in term of efficacy and toxicity. From this experimental design it could be concluded that further modification of this prototypical structure will lead to develop more potent antioxidant as well as anticancer agent in futureTherefore, the series requires to be well extended. Thus, it could be concluded that the synthesized 1,2,4-triazole linked hydroxamic acid derivatives with electron donating groups at 5-position of the 1,2,4-triazole moiety may provide a therapeutically effective chemical framework from which potential antimicrobial as well as antileishmanial agents may be developed further. Therefore, further optimizations of this prototypical molecular framework with some diversified molecular fragments may generate new drug entities having potent biological activities.