Chakka Sai Kumar, Kalamuddin Mohammad, Sundararaman Srividhya, Wei Lianhu, Mundra Sourabh, Mahesh Radhakrishnan, Malhotra Pawan, Mohmmed Asif, Kotra Lakshmi P
Center for Molecular Design and Preformulations, and Toronto General Research Institute, University Health Network, #5-356, Toronto Medical Discoveries Tower/MaRS Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
International Centre for Genetic Engineering & Biotechnology, Aruna Asif Ali Marg, New Delhi 100 067, India.
Bioorg Med Chem. 2015 May 1;23(9):2221-40. doi: 10.1016/j.bmc.2015.02.062. Epub 2015 Mar 18.
Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature (1)H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (Ki) of 1.8 ± 1.1, 0.2 ± 0.1 and 7.0 ± 2.3 μM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (Ki=0.4 ± 0.1, 2.5 ± 0.5, 3.3 ± 1.1, 7.5 ± 1.9, and 4.6 ± 0.7 μM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC₅₀=0.9 ± 0.1 μM), corresponding with its inhibitory activity against falcipain-2, with a Ki of 1.1 ± 0.1 μM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12-fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents.
疟原蛋白酶-2是一种木瓜蛋白酶家族的半胱氨酸蛋白酶，也是一个新兴的抗疟药物靶点。使用计算机筛选工具以及疟原蛋白酶-2、疟原蛋白酶-3和木瓜蛋白酶的三维结构设计了一种假三肽支架I。在四个位置T1、T2、T3和T3'对该支架进行了研究，进行了各种靶向取代以了解构效关系。抑制剂的合成首先通过获得具有共同结构成分的合适二肽前体来完成。吡咯烷部分在许多合成分子中引入了有趣的旋转异构体，这通过高温（1）H核磁共振光谱得到了证实。在合成的化合物中，61、62和66抑制疟原蛋白酶-2的活性，抑制常数（Ki）分别为1.8±1.1、0.2±0.1和7.0±2.3μM。一组在T2位置带有吡咯烷部分的分子（68、70、71、72和73）也有效抑制疟原蛋白酶-2的活性（Ki分别为0.4±0.1、2.5±0.5、3.3±1.1、7.5±1.9和4.6±0.7μM）。总体而言，化合物74表现出强大的抗寄生虫活性（IC₅₀=0.9±0.1μM），与其对疟原蛋白酶-2的抑制活性相对应，Ki为1.1±0.1μM。化合物62和67对耐药寄生虫Dd2的生长抑制效果更好，并且化合物74对Dd2和MCamp分离株的效力比对实验室菌株（3D7）高7至12倍。这些数据表明，这一系列新型化合物应作为潜在的抗疟药物进行进一步研究。
