Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

摘要

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over1 million individuals worldwide. Treatment options for leishmaniasisare limited due to high cost, severe adverse effects, poor efficacy,difficulty of use, and emerging drug resistance to all approved therapies.We discovered 2,4,5-trisubstituted benzamides (4) thatpossess potent antileishmanial activity but poor aqueous solubility.Herein, we disclose our optimization of the physicochemical and metabolicproperties of 2,4,5-trisubstituted benzamide that retains potency.Extensive structure-activity and structure-propertyrelationship studies allowed selection of early leads with suitablepotency, microsomal stability, and improved solubility for progression.Early lead 79 exhibited an 80 oral bioavailability andpotently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for developmentas orally available antileishmanial drugs.