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
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potent HIV-1 IN inhibitors (unpublished results from our laboratory).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. Prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine
derivatives 10-12 and tyrphostin 13.
Results: 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.