Parveen Seheli, Khan Mohammed O F, Austin Susan E, Croft Simon L, Yardley Vanessa, Rock Peter, Douglas Kenneth T
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
J Med Chem. 2005 Dec 15;48(25):8087-97. doi: 10.1021/jm050819t.
Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition approximately 40-fold (3',4'-dichlorobenzyl-[5-chloro-2-phenylsulfanyl-phenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 +/- 0.2 microM). 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 (Ki, Ki' = 11.3-42.8 microM). 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-amino-4-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.
氯丙嗪的2-氨基-4-氯苯基苯硫醚类似物的氮原子季铵化使抑制作用提高了约40倍（3',4'-二氯苄基-[5-氯-2-苯基硫基-苯基氨基]-丙基]-二甲基氯化铵抑制克氏锥虫的锥虫硫醇还原酶，线性竞争Ki值为1.7±0.2 microM）。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（大致由F396'、P398'和L399'界定）的参与，(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-氯苯基硫醚表现出混合抑制作用（Ki，Ki' = 11.3 - 42.8 microM）。2-氯苯基苯硫醚的季铵化类似物在体外对罗德西亚布氏锥虫STIB900、克氏锥虫图拉万株和杜氏利什曼原虫HU3具有很强的抗锥虫和抗利什曼原虫活性。N-酰基-2-氨基-4-氯苯基硫醚对恶性疟原虫有活性。吩噻嗪和二芳基硫醚季铵化合物也是强大的抗疟药，为抗疟药物设计提供了新的结构框架。
