The main aim of the project was the development of M. avium EP inhibitors (EPIs) able to synergize the activity of antibacterial agents that are now in use. By exploiting a multidisciplinary approach including drug-design, chemical synthesis, and biological evaluations, the researchers performed the chemical optimization of compounds with a 3-phenylquinolone scaffold previously identified as M. avium EPIs. The compounds designed and synthesized have been preliminarily tested against M. smegmatis to evaluate EPI activity and on human cells (macrophages) to determine toxicity. The best compounds in terms of toxicity/activity ratio have been advanced against M. avium. These studies have led to the identification of some new molecules with a high inhibitory potency of EPIs. One of these in particular, is able to enhance the activity of antibiotics such as clarithromycin, which is a drug of choice for the NTM infections treatment, and ciprofloxacin against M. avium, at lower concentrations than those toxic to macrophages. Considering the field of NTMs EPIs, this compound has the best toxicity/activity profile and can represent a new starting point for further optimization aimed at identifying preclinical candidates.

 Congress abstracts

– Cannalire R, Felicetti T, Nizi MG et al. “Design, synthesis, and biological evaluation of functionlized 3-phenylquinolones to block efflux machinery in non-tubercolous mycobacteria” Italian-Spanish-Portuguese Joint Meeting in Medicinal Chemistry, MedChemSicily2018, Palermo, July 17-20, 2018
– Felicetti T, Cannalire R, Machado D et al. “New potent and safer functionalized 3-phenylquinolones as efflux inhibitors of the Mycobacterium avium” Italian-Spanish-Portuguese Joint Meeting in Medicinal Chemistry, MedChemSicily2018, Palermo, July 17-20, 2018