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

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Leishmania* ; Leishmaniasis*/drug therapy ; Leishmaniasis*/chemically induced ; Leishmaniasis*/parasitology ; Antiprotozoal Agents*/chemistry; Humans ; Animals ; Mice ; Benzamides/pharmacology ; Benzamides/therapeutic use

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.

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R33 AI127591 United States AI NIAID NIH HHS; S10 OD028690 United States OD NIH HHS

6X80438640 (benzamide)
0 (Antiprotozoal Agents)
0 (Benzamides)

Date Created: 20230522 Date Completed: 20230609 Latest Revision: 20240523

20240523

PMC10259451

10.1021/acs.jmedchem.3c00056

37216489