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

Ho Shin Kim, Diana Ortiz, Tara Man Kadayat, Corinne M Fargo, Jared T Hammill, Yizhe Chen, Amy L Rice, Kristin L Begley, Gaurav Shoeran, William Pistel, Phillip A Yates, Marco A Sanchez, Scott M Landfear, R Kiplin Guy

Research output: Contribution to journalArticlepeer-review


Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are 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) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Original languageEnglish
Pages (from-to)7374-7386
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number11
StatePublished - Jun 8 2023


  • Humans
  • Animals
  • Mice
  • Leishmania
  • Leishmaniasis/drug therapy
  • Antiprotozoal Agents/chemistry
  • Benzamides/pharmacology


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