In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species

作者：Nieto Meneses Roclo; Castillo Rafael; Hernandez Campos Alicia; Maldonado Rangel Armando; Matius Ruiz Jeferson B; Trejo Soto Pedro Josue; Nogueda Torres Benjamin; Dea Ayuela Ma Auxiliadora; Bolas Fernandez Francisco; Mendez Cuesta Carlos; Yepez Mulia Lilian^*

来源：Experimental Parasitology, 2018, 184: 82-89.

DOI：10.1016/j.exppara.2017.11.009

• Benzimidazole derivatives
• Antileishmanial activity
• Selectivity Index
• Arginase

The identification of specific therapeutic targets and the development of new drugs against leishmaniasis are urgently needed, since chemotherapy currently available for its treatment has several problems including many adverse side effects. In an effort to develop new antileishmanial drugs, in the present study a series of 28 N-benzyl-1H-benzimidazol-2-amine derivatives was synthesized and evaluated in vitro against Leishmania mexicana promastigotes. Compounds 7 and 8 with the highest antileishmanial activity (micromolar) and lower cytotoxicity than miltefosine and amphotericin B were selected to evaluate their activity against L braziliensis 9 and L donovani, species causative of mucocutaneous and visceral leishmaniasis, respectively. Compound 7 showed significantly higher activity against L. braziliensis promastigotes than compound 8 and slightly lower than miltefosine. Compounds 7 and 8 had 1050 values in the micromolar range against the amastigote of L mexicana and L braziliensis. However, both compounds did not show better activity against L donovani than miltefosine. Compound 8 showed the highest SI against both parasite stages of L mexicana. In addition, compound 8 inhibited 68.27% the activity of recombinant L mexicana arginase (LmARG), a therapeutic target for the treatment of leishmaniasis. Docking studies were also performed in order to establish the possible mechanism of action by which this compound exerts its inhibitory effect. Compound 8 shows promising potential for the development of more potent antileishmanial benzimidazole derivatives.

• 出版日期2018-1