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

Abstract

Background: HIV-1 integrase (IN) has been considered as an important target for the development of novel anti-HIV-1 drugs.

Objective: The aim of this study was to design novel groups of HIV IN inhibitors.

Methods: 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 β-diketoacids as a well-known group of IN inhibitors.

Results: Based on in-vitro anti-HIV-1 activity in a 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 μM, respectively. However, integrase inhibition assay showed that most of the analogues did not have significant effects against integrase enzyme except compound 5 with an IC50 value of 45 μM. Our results indicated that compound 6k was the best one among synthesized compounds with an EC₅₀ of 0.8 μM and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into the 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 the development of new anti-HIV-1 drugs.

Keywords: HIV-1 integrase; Human Immunodeficiency Virus type 1 (HIV-1).; benzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid; docking; molecular dynamics; synthesis.