Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide
Antitrypanosomal, antileishmanial, and antimalarial activities of quaternary arylalkylammonium 2-amino-4-chlorophenyl phenyl sulfides, a new class of trypanothione reductase inhibitor, and of N-acyl derivatives of 2-amino-4-chlorophenyl phenyl sulfide
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DOI：
10.1021/jm050819t
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发表时间：
2005-12-15
影响因子：
7.3
通讯作者：
Douglas, KT
中科院分区：
文献类型：
--
作者：
Parveen, S;Khan, MOF;Douglas, KT
氯丙嗪的2-氨基-4-氯苯基苯基硫醚类似物的氮原子的三甲基化改善了抑制作用，类似于40倍（3 ′，4 ′-二氯苄基-[5-氯-2-苯硫基-苯基氨基）-丙基]-二甲基氯化铵抑制来自克氏锥虫的锥虫硫酮还原酶，线性竞争性Ki值为1.7 +/-0.2 μ M）。分子建模通过以下方式解释了对接方向和能量：（i）Z位点疏水口袋的参与（大致由F396 '、P398'和L399'界定）（ii）阳离子氮与Glu-466'或-467 '的离子相互作用。一系列N-酰基-2-氨基-4-氯苯硫醚表现出混合抑制作用（Ki，Ki ′ = 11.3-42.8 μ M）。2-氯苯基苯硫醚的季铵化类似物具有较强的体外抗锥虫和利什曼原虫活性。brucei rhodesiense STIB900、T. cruzi Tulahuan和杜氏利什曼原虫HU 3。N-酰基-2-氨基-4-氯苯硫醚具有抗恶性疟原虫活性。吩噻嗪和二芳基硫醚季铵化合物也是有效的抗疟药，为抗疟药的设计提供了一个新的结构框架。
Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition similar to 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive K-i value of 1.7 +/- 0.2 mu M). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396', P398', and L399' (ii) ionic interactions for the cationic nitrogen with Glu-466' or -467'. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (K-i, K-i' = 11.3-42.8 mu M). The quaternized analogues of the 2-chlorophenyl phenyl sulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. brucei rhodesiense STIB900, T. cruzi Tulahuan, and Leishmania donovani HU3. The N-acyl-2-amino4-chlorophenyl sulfides were active against Plasmodium falciparum. The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.