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Antimalarial Dibenzannulated Medium-Ring Keto Lactams.

Authors :
Ren R
Wang X
Leas DA
Scheurer C
Hoevel S
Cal M
Chen G
Zhong L
Katneni K
Pham T
Patil R
Sil D
Walters MJ
Schulze TT
Neville AJ
Dong Y
Wittlin S
Kaiser M
Davis PH
Charman SA
Vennerstrom JL
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