Abstract
Tetrazole derivatives containing nitro substituents have been identified as promising antitubercular agents. In this study, the antitubercular potency, selectivity and toxicity of tetrazole 1,5- and 2,5-regioisomers were examined.
We prepared a series of 1-and 2-alkyl-5-benzylsulfanyl-2H-tetrazoles and their selenium analogs with various nitro group substitutions. These 1,5-and 2,5-regioisomers were isolated and unambiguously identified using H-1 and/or C-13 NMR.
Among the prepared compounds, 1-and 2-alkyl-5-[(3,5-dinitrobenzyl) sulfanyl]-2H-tetrazole derivatives and their selenium bioisosteres showed the highest antimycobacterial activity, with minimal inhibitory concentration (MIC) values of approximately 1 mu M (0.37-0.46 mu g mL(-1)) against Mycobacterium tuberculosis CNCTC My 331/88. The 2-alkyl regioisomers exhibited consistently higher antimycobacterial activity and lower in vitro toxicity against a mammalian cell line compared to the 1-alkyl isomers.
The antimycobacterial activity of the 2-alkyl regioisomers was less influenced by the type of alkyl substituent in contrast to 1-alkyl isomers. Furthermore, the 3,5-dinitrobenzyl moiety per se is not the carrier of mutagenicity.
These findings encourage further optimization of the 2-alkyl chain to improve the pharmacokinetic properties and toxicity of 2-alkyl-5-[( 3,5-dinitrobenzyl) sulfanyl]-2H-tetrazole lead compounds.