Novel 4-Oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic Acid Derivatives as HIV-1 Integrase Inhibitors: Synthesis, Docking studies, Molecular Dynamics Simulation and Biological Activities.

BACKGROUND HIV-1 integrase (IN) has been considered as an important target for the development of novel antiHIV-1 drugs. OBJECTIVE The aim of study is to design a novel groups of HIV IN inhibitors. METHOD In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole -diketoacids as a well-known group of IN inhibitors. RESULTS Based on in-vitro anti-HIV-1 activity in cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC50 values of 4.14, 1.68 and 0.8 M, respectively. However, integrase inhibition assay showed that most of analogues did not have significant effects against integrase enzyme except compound 5 with IC50 value of 45 M. Our results indicated that compound 6k was the best one among synthesized compounds with an EC50 of 0.8 M and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into probable mechanism of tested compounds. CONCLUSION These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives may consider as promising lead compounds for development of new anti-HIV-1 drugs.