Maignan Jordany R, Lichorowic Cynthia L, Giarrusso James, Blake Lynn D, Casandra Debora, Mutka Tina S, LaCrue Alexis N, Burrows Jeremy N, Willis Paul A, Kyle Dennis E, Manetsch Roman
Department of Chemistry, University of South Florida , CHE 205, 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
Department of Chemistry and Chemical Biology, Northeastern University , 102 Hurtig Hall, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
J Med Chem. 2016 Jul 28;59(14):6943-60. doi: 10.1021/acs.jmedchem.6b00759. Epub 2016 Jul 12.
Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.
自2000年以来，全球疟疾死亡率下降了48%，但报告显示，对现有疗法产生耐药性的情况有可能使这一进展逆转。最近，人们重新审视了一些曾被认为不合适的抗疟药物，以改善其物理化学性质和作为候选药物所需的疗效。其中一种化合物是4(1H)-喹诺酮ICI 56,780，它已知是一种病因性预防药物，对伯氏疟原虫也具有血液裂殖体杀灭活性。然而，寄生虫耐药性的迅速产生阻碍了它的进一步研发。我们完成了一项针对4(1H)-喹诺酮的全面构效关系研究，重点是减少与阿托伐醌的交叉耐药性，以提高对临床分离株W2和TM90-C2B的活性，以及改善微粒体稳定性。这些研究揭示了几种具有出色体内抗疟活性的领先化合物。发现最好的化合物具有治愈效果，所有感染伯氏疟原虫的小鼠在30天后均存活下来。
