Open AccessSynthesis and Antileishmanial Evaluation of Arylimidamide–Azole Hybrids Containing a Phenoxyalkyl Linker
Author(s) -
Ahmed Abdelhameed,
Mei Feng,
April C. Joice,
Emilia M. Zywot,
Yiru Jin,
Chris La Rosa,
XiaoPing Liao,
Heidi L. Meeds,
Yena Kim,
Junan Li,
Craig A. McElroy,
Michael Zhuo Wang,
Karl A. Werbovetz
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.0c00855
Subject(s) - leishmania donovani , visceral leishmaniasis , azole , linker , pharmacology , amastigote , leishmaniasis , imidazole , leishmania , potency , chemistry , stereochemistry , biology , biochemistry , in vitro , immunology , antifungal , microbiology and biotechnology , parasite hosting , computer science , world wide web , operating system
Due to the limitations of existing medications, there is a critical need for new drugs to treat visceral leishmaniasis. Since arylimidamides and antifungal azoles both show oral activity in murine visceral leishmaniasis models, a molecular hybridization approach was employed where arylimidamide and azole groups were separated by phenoxyalkyl linkers in an attempt to capitalize on the favorable antileishmanial properties of both series. Among the target compounds synthesized, a greater antileishmanial potency against intracellular Leishmania donovani was observed as the linker length increased from two to eight carbons and when an imidazole ring was employed as the terminal group compared to a 1,2,4-triazole group. Compound 24c ( N -(4-((8-(1 H -imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide) displayed activity against L. donovani intracellular amastigotes with an IC 50 value of 0.53 μM. When tested in a murine visceral leishmaniasis model, compound 24c at a dose of 75 mg/kg/day p.o. for five consecutive days resulted in a modest 33% decrease in liver parasitemia compared to the control group, indicating that further optimization of these molecules is needed. While potent hybrid compounds bearing an imidazole terminal group were also strong inhibitors of recombinant CYP51 from L. donovani , as assessed by a fluorescence-based assay, additional targets are likely to play an important role in the antileishmanial action of these compounds.