El Ghozlani M, Bouissane L, Berkani M, Mojahidi S, Allam A, Menendez C, Cojean S, Loiseau P M, Baltas M, Rakib E M
Laboratoire de Chimie Organique et Analytiques , Faculté des Sciences et Techniques , Université Sultan Moulay Slimane , B.P. 523, Béni-Mellal , Morocco . Email:
Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique , Université Paul Sabatier , UMR-CNRS 5068, 118 route de Narbonne , 31062 Toulouse cedex 9 , France.
Medchemcomm. 2018 Nov 19;10(1):120-127. doi: 10.1039/c8md00475g. eCollection 2019 Jan 1.
A series of novel indazole-pyrone hybrids were synthesized by a one pot reaction between -alkyl-6(5)-nitroindazoles and 2-pyrone (4-hydroxy-6-methyl-2-pyran-2-one) using indium or stannous chloride as the reducing system in the presence of acetic acid in tetrahydrofuran. The hybrid molecules were obtained in good to excellent yields (72-92%) and characterized by NMR and single crystal X-ray diffraction. Nineteen compounds were tested against both (MHOM/ET/67/HU3, also called LV9) axenic and intramacrophage amastigotes. Among all, five compounds showed anti-leishmanial activity against intracellular with an IC in the range of 2.25 to 62.56 μM. 3-(1-(3-Chloro-2-ethyl-2-indazol-6-ylamino)ethylidene)-6-methyl-3-pyran-2,4-dione was found to be the most active compound for axenic amastigotes and intramacrophage amastigotes of with IC values of 2.48 ± 1.02 μM and 2.25 ± 1.89 μM, respectively. However, the cytotoxicity of the most promising compound justifies further pharmacomodulations.
通过在四氢呋喃中，以铟或氯化亚锡作为还原体系，在乙酸存在下，使-烷基-6(5)-硝基吲唑与2-吡喃酮（4-羟基-6-甲基-2-吡喃-2-酮）进行一锅反应，合成了一系列新型吲唑-吡喃酮杂化物。杂化分子的产率良好至优异（72-92%），并通过核磁共振和单晶X射线衍射进行了表征。对19种化合物针对无细胞的（MHOM/ET/67/HU3，也称为LV9）和巨噬细胞内无鞭毛体进行了测试。其中，五种化合物对细胞内的表现出抗利什曼原虫活性，IC值在2.25至62.56μM范围内。发现3-(1-(3-氯-2-乙基-2-吲唑-6-基氨基)亚乙基)-6-甲基-3-吡喃-2,4-二酮是对无细胞无鞭毛体和巨噬细胞内无鞭毛体最具活性的化合物，IC值分别为2.48±1.02μM和2.25±1.89μM。然而，最有前景的化合物的细胞毒性证明需要进一步进行药效调节。
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