Robenidine Analogues as Gram-Positive Antibacterial Agents

Journal of Medicinal Chemistry
Rebecca J AbrahamDarren Trott

Abstract

Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 μM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)3 (27) (23.7-71 μM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 μM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 μL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.

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Citations

May 28, 2016·Expert Opinion on Drug Discovery·Ya-Jun Zheng, Colin M Tice
Oct 3, 2017·Natural Product Reports·Roberto G S BerlinckJulie P G Rodriguez
Jul 10, 2018·Current Medicinal Chemistry·Ananda Kumar KonreddyYongseok Choi
Apr 25, 2019·International Journal for Parasitology. Drugs and Drug Resistance·Rebecca J AbrahamRyan M O'Handley
Feb 23, 2021·Frontiers in Microbiology·Xiufeng ZhangZhenling Zeng
Mar 17, 2021·ACS Infectious Diseases·Alina KrollenbrockMichael K Riscoe
Mar 23, 2021·International Journal of Antimicrobial Agents·Hang Thi NguyenDarren J Trott

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