Aim: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4-
tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors.
Background: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent
of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease
play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human
chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed
as the “point of no-return” in HIV infection.
Objective: To develop inhibitors against HIV integrase strand transfer step.
Methods: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors
(unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4-
oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1
Integrase strand transfer. As shown in figure 2, prototype compound 14 can be viewed as hybrid structure having characteristics
of dihydropyrimidine derivatives 10-12 and tyrphostin 13.
Result: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The
percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds
was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version
9.3, Schrödinger suite) in extra precision (XP) mode.
Conclusion: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized
and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage
inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active
against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored
further for their anti-HIV or cytotoxic potential.