The Direct-Acting Mutagenicity of Nitrothiophenes Derivatives in Salmonella Typhimurium

Abstract

Nitroheterocyclic drugs have in recent years become of great interest for their mutagenicity and carcinogenicity. A series of nitrocompounds (structurally-related to the 5-nitro-3-thiophenecarboxylic acid) were synthesized as chemotherapeutic agents and assayed for their direct-acting and S9 mediated mutagenicity in Salmonella typhimurium TA100 and TA98 strains. Effects of different substituents, such as NO2, Cl, Br, F, CH3 and OCH3 groups, were studied to evaluate the structural feature that affects the metabolism and the bacterial mutagenic potency of nitrothiophenes. All the derivatives were found to be mutagenic, TA100 was the most sensitive strain. Increased activity was shown by substituted compounds; the Br derivatives were the weakest mutagens, Cl and NO2 compounds exhibited the most dramatic mutagenicity. The mutagenic activity did not require the S9 fraction but was largely dependent on bacterial nitroreductase. The primary basis of nitrothiophene direct-acting mutagenicity appears to be a reduction of the nitrofunction to the corresponding hydroxylamine, via diamagnetic and free radical intermediates. The determination of physico-chemical parameters, as expression of the liphophilic character of the molecules, will contribute to carry out structure-activity studies in order to recognize the base structure for the receptor-drug binding.