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Antimalarial Dibenzannulated Medium-Ring Keto Lactams.
- Source :
-
ACS infectious diseases [ACS Infect Dis] 2023 Oct 13; Vol. 9 (10), pp. 1964-1980. Date of Electronic Publication: 2023 Sep 11. - Publication Year :
- 2023
-
Abstract
- We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5 H -dibenzo[ b , g ]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD <subscript>7.4</subscript> values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD <subscript>7.4</subscript> values of <2) had the best metabolic stability (CL <subscript>int</subscript> values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC <subscript>50</subscript> values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC <subscript>50</subscript> values of 4.2 to 9.4 nM and in vitro selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens ( Trypanosoma brucei rhodesiense , Trypanosoma cruzi , and Leishmania donovani ) but did have relatively high potency against Toxoplasma gondii , with IC <subscript>50</subscript> values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1 H )-quinolone transannular condensation products in vitro in culture medium and in vivo in mouse blood. The similar antiplasmodial potencies of three keto lactam-quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.
Details
- Language :
- English
- ISSN :
- 2373-8227
- Volume :
- 9
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- ACS infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 37695781
- Full Text :
- https://doi.org/10.1021/acsinfecdis.3c00245