Fexinidazole optimization: enhancing anti-leishmanial profile, metabolic stability and hERG safety

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.