Discovery of quinolinequinones with N-phenylpiperazine by conversion of hydroxyquinoline as a new class of antimicrobial agents targeting resistant pathogenic microorganisms

Abstract

The development of new antimicrobial agents is necessary to overcome the emerging antimicrobial resistance among infectious microbial pathogens. Herein, we successfully designed and synthesized quinolinequinones (QQs) with N-phenylpiperazine (QQ1-7) containing strong or weak EDG in the amino moiety by converting hydroxyquinoline (HQ) to the dichloroquinolinequinone (QQ) via chlorooxidation. We performed an extensive antimicrobial activity assessment of the QQs with N-phenylpiperazine (QQ1-7). Among the seven quinolinequinones (QQs) with N-phenylpiperazine tested, QQ3 and QQ4 were the most active molecules against Staphylococcus aureus (ATCC (R) 29213) with a MIC value of 1.22 mu g/mL. In addition to this, while QQ4 was more than six (6) times more effective towards Enterococcus faecalis (ATCC (R) 29212), QQ3 was twenty-six (26) times more effective against same strain. Furthermore, the evaluation of antimicrobial activity indicated that six of seven synthesized QQs (QQ1-4, QQ6, and QQ7) exhibited superior biological potency, eight (8) times for five of them (QQ1-4 and QQ6) and two (2) times for QQ7, against Staphylococcus epidermidis (ATCC (R) 12228). Besides, all QQs except QQ5 displayed excellent antifungal activity against the fungi Candida albicans (ATCC (R) 10231). Among these, the two QQs (QQ3 and QQ4), which showed the lowest values against gram-positive bacterial strains (Staphylococcus aureus (ATCC (R) 29213), Staphylococcus epidermidis (ATCC (R) 12228), and Enterococcus faecalis (ATCC (R) 29212)) as well as fungal strains (Candida albicans (ATCC (R) 10231) and Candida parapsilosis (ATCC (R) 22019)), were further evaluated for their biofilm inhibition properties and their mode of action with in vitro potential antimicrobial activity against each of 20 clinically obtained resistant strains of gram-positive bacteria, and bactericidal activity using time-kill curve assay. In this study, we investigated the bactericidal effects of QQ3 against methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans strains. The findings of this study suggest that a significant bactericidal effect was seen with all tested 1 x MIC and 4 x MIC concentrations used within 24 h. Our findings present significant implications for an antimicrobial drug candidate for treating infections, especially those caused by clinically resistant MRSA isolates.