Makhija Mahindra T, Kasliwal Rajesh T, Kulkarni Vithal M, Neamati Nouri
Pharmaceutical Division, Department of Chemical Technology, University of Mumbai, Matunga, Mumbai 400019, India.
Bioorg Med Chem. 2004 May 1;12(9):2317-33. doi: 10.1016/j.bmc.2004.02.005.
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.
现有的艾滋病疗法对于发展中国家的大多数艾滋病毒感染者来说遥不可及，而且即便有这些疗法，它们也受到毒性和成本的限制。迫切需要新的抗艾滋病毒药物来对抗新出现的病毒耐药性，并减少与现有药物相关的副作用。为此，采用了从头药物设计程序LeapFrog来设计新型、高效且具有选择性的HIV-1整合酶抑制剂。合成了所设计的化合物，并对其进行体外抑制HIV-1整合酶的测试。在设计并合成的25种化合物中，有4种分子（化合物23、26、43和59）对HIV-1整合酶的3'-加工和3'-链转移活性表现出中度至低度抑制。尽管如此，这些化合物具有已知HIV-1整合酶抑制剂中未见的结构特征，因此可作为进一步优化抗HIV-1整合酶活性的优良先导物。
