De novo design and synthesis of HIV-1 integrase inhibitors |
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Authors: | Makhija Mahindra T Kasliwal Rajesh T Kulkarni Vithal M Neamati Nouri |
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Institution: | Pharmaceutical Division, Department of Chemical Technology, University of Mumbai, Matunga, Mumbai 400019, India. m.makhija@exchange.curtin.edu.au |
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Abstract: | Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3'-processing and 3'-strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity. |
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