Abstract

To develop new and potent therapies against human immunodeficiency virus infections, a series of 3-acetyl- 2H-1-benzopyran-2-one derivatives (2a-n) were synthesized and evaluated for lens epithelium-derived growth factor/p75-dependent human immunodeficiency virus type-1 integrase inhibition activity. Knoevenagel reaction of o-hydroxy-benzaldehyde with a stable enolate initially formed a diester, which after transesterification formed 1 (3-acetyl-2H-1-benzopyran-2-one) as an intermediate. Claisen-Schmidt condensation of 1, with substituted bezaldehydes, lacking an alpha-hydrogen, using silica sulphuric acid as a catalyst formed 2an. In silico absorption, distribution, metabolism and excretion parameters of 2a-n were calculated, which were found well within their reference limits. In silico toxicity risk assessment showed that all synthesized compounds possess low toxicity risks for irritant effect, mutagenicity, reproductive effect and tumorigenicity. Amongst all synthesized compounds, 2a, 2g and 2h showed human immunodeficiency virus type-1 integrase inhibition with half-maximal inhibitory concentration value of 86.5, 90.0 and 98.5 μM respectively. Structure activity relationship showed that electron-withdrawing group at phenyl ring, attached to the benzopyran-2- one nucleus was important for human immunodeficiency virus type-1 integrase inhibition activity. Molecular docking study showed that the binding pattern of 2a-n in the binding pocket of human immunodeficiency virus type-1 integrase is similar to that of raltegravir. The findings of the present study may help in design and development of potent human immunodeficiency virus type-1 integrase inhibitors as novel antiretroviral agent.