Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
J Med Chem. 2011 Jul 14;54(13):4581-9. doi: 10.1021/jm200227r. Epub 2011 Jun 16.
A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.
一类新型抗疟吡啶并[1,2-a]苯并咪唑类化合物被合成，并对从商业上可获得的化合物库中筛选出的命中化合物进行抗疟原虫活性和细胞毒性评估。其中最活跃的化合物 TDR86919（4c）对耐氯喹的恶性疟原虫 K1 株的体外活性较氯喹（IC（50）= 0.047 μM 比 0.17 μM）有所提高；对一系列敏感和耐药株的活性保持不变，对哺乳动物（L-6）细胞系的细胞毒性可忽略不计（选择性指数 >600）。4c 和几种类似物（HCl 或甲磺酸盐）在经腹腔（ip）和口服（po）给药后对感染伯氏疟原虫的小鼠具有显著疗效，寄生虫血症抑制率>90%，并伴有平均存活时间（MSD）延长。与氯喹相比，吡啶并[1,2-a]苯并咪唑类化合物在体内的作用似乎相对较慢，并且侧链的烷基氨基代谢稳定性被确定为影响体内活性的关键因素。
