Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2023-06, Vol.66 (11), p.7374-7386

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.