سنتز، فعالیت ضد لیشمانیایی و داکینگ مولکولی تعدادی از مشتقات 3و4-دی هیدروپیریمیدینون/تیون

عنوان انگليسی

SYNTHESIS, ANTILEISHMANIAL ACTIVITY AND MOLECULAR DOCKING STUDY OF NEW 3,4-DIHYDROPYRIMIDINONES/THIONES

خلاصه انگلیسی

Appearance of drug-unresponsive strains of Leishmania genus and toxic side effects of current chemotherapies necessitate the search for novel antileishmanial agents. Within present contribution, new dihydropyrimidine/thione-5-carboxylates/carboxamide derivatives were synthesized and biologically assessed against Leishmania major promastigotes. A few derivatives exhibited promising antileishmanial activities (IC(50)s 24.7 - 2223.9 mu M). Results of biological assessment revealed compound 4 as the most potent antileishmanial agent. Compounds 1, 3, 4, 8 and 9 exhibited significant activity with regard to Glucantime (control drug). For both 5-carboxamide and 5-carboxylate series, it was found that steric hindrance of 4-(3-substituted phenyl) position was determinant in antileishmanial effect proposing a hydrophobic pocket near meta position of 4-phenyl moiety. Molecular docking approach vs. pteridine reductase 1 as a validated leishmanial target revealed that 5-carboxylate derivatives made H-bond with enzyme cofactor, i.e., nicotinamide adenine dinucleotide phosphate (NDP602). Interaction pattern was relatively similar to previously reported drugs such as trimethoprim. Binding efficiency indices (BEIs) were in accordance with antileishmanial IC50 values.

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