Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

Abstract

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

“…The 3,4‐dichloro‐5‐methyl‐1 H ‐pyrrole was selected because the chlorine atoms are slightly smaller than the bromine atoms and are thus proposed to bind more strongly, not only to E. coli DNA gyrase, but also to the slightly smaller binding pockets of Staphylococcus aureus DNA gyrase and topoisomerase IV . Additionally, the 3,4‐dichloro‐5‐methylpyrrole moiety is found, for example, in kibdelomycin, a complex antibiotic isolated from extracts of the soil bacterium Kibdelosporangium sp., and in some pyrrolamide DNA gyrase B inhibitors developed by AstraZeneca …”

Synthesis and structure–activity relationship of N4-benzylamine-N2-isopropyl-quinazoline-2,4-diamines derivatives as potential antibacterial agents

“…The methods of the ve assays, including log D 7.4 , aqueous solubility, plasma protein binding, microsome and hepatocyte clearance measurements has been reported previously (Basarab et al, 2014 and Doyle et al, 2016) and are described briey as below 34,35 . log D 7.4 Determination assay.…”

Design of Antibacterial Agents

“…At the same time, parameters such as clearance and plasma protein binding were optimized towards translating the activity from in vitro to in vivo. Among other substituents in place of the fluorine atom that improved biological activity was a methoxyl group that made a closer hydrophobicÀhydrophobic contact with the enzyme [106]. IC 50 : the concentration that inhibited the DNA gyrase of S. aureus by 50%; MICs were measured against S. aureus.…”