Abstract
The lack of adequate anti-leishmanial therapies has led to the continued suffering of millions of people from developing nations. Moreover, optimism for a therapeutic intervention by fexinidazole was dashed due to the inability to maintain cures and control unwanted side effects. To solve these shortcomings, the structural elements of fexinidazole responsible for anti-leishmanial activity and toxicities were explored. Accordingly, a systematic analog design approach was taken for the synthesis of 24 novel analogs. We established the structural features important for activity and identified modifications that improved the hERG receptor safety and liver microsomal metabolic stability. Compared to fexinidazole, the S-configured imidazolooxazole analog 51 exhibited 25-fold greater potency against miltefosine resistant L. donovani amastigotes, greater metabolic stability and little hERG receptor inhibition. Replacement of the toxicophore nitro group for a cyano group resulted in a complete loss of anti-leishmanial activity. The SAR findings should be useful in the further development of this important class of anti-leishmanial agents.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
