Background: HIV-1 protease is a prime target for drug therapy due to its integral role in
HIV viral replication. Several protease inhibitors such as lopinavir and tipranavir were shown to possess
potent inhibitory activities against the HIV virus. Due to the high mutation rate of HIV, resistance
remains a major problem in the treatment of this virus and design and synthesis of new protease inhibitors
is an area of continued interest in new drug discovery research.
Methods: Utilizing the key fragments of structures of both peptide-based and non-peptide-based protease
inhibitors lopinavir and tipranavir, we explored designing some new compounds.
Results: Six new protease inhibitors were designed and synthesized based on the key structural fragments
in lopinavir and tipranavir. The designed new compounds contain heterocyclic groups such as
thiophene, isoxazole, and imidazole groups, and the best compound exhibited 0.6 nm of the protease
Conclusion: We have prepared some novel heterocyclic sulfonamides utilizing a key fragment based
approach by recombining structural fragments of the potent protease inhibitors lopinavir and tipranavir.
Some of these newly designed compounds showed good to excellent HIV-1 protease inhibitory activity,
which indicated that this method would be useful for the discovery of new drug lead compounds
that target HIV.