, Volume 22, Issue 5, pp 2467-2475
Date: 28 Sep 2012

Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted 4-oxo-4H -pyrido[1,2-a ]pyrimidines as anti-HIV-1 agents

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A new series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives containing 1,3,4-oxadiazole and 1,3,4-thiadiazole rings as a part of the metal chelation motif were synthesized and evaluated for their in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate inhibitory properties against HIV-1 virus (NL4-3) in Hela cell cultures. Compounds 11e and 11b exhibited the highest activity among the synthesized compounds with inhibition rate of 51 and 48 % at concentration of 100 μM, respectively. Molecular docking study using the later crystallographic data available for PFV integrase (IN) showed that the designed compounds bind into the active site of IN such that the keto oxygen atom at position of C-4 and nitrogen atom of thiadiazole or oxadiazole ring moiety chelate the Mg2+ ion. Our results also showed that all tested compounds presented no significant cytotoxicity at concentration of 100 μM. Therefore, these compounds can provide a very good basis for the development of new hits.