Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma— <i>en route</i> to broad-spectrum antimycetomal drugs

Abstract

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as <i>Madurella mycetomatis</i>, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to <i>in vitro</i> screening against two fungal strains of <i>M. mycetomatis</i> and three bacterial strains of <i>Actinomadura madurae</i> and <i>A. syzygii</i>. Seven NIQs, mostly dimers, showed promising <i>in vitro</i> activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-<i>O</i>,<i>O</i>-dimethylmichellamine A (<b>18</b>), inhibited all tested fungal and bacterial strains (IC₅₀ = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (<b>14</b>), inhibited a strain of <i>M. mycetomatis</i> and significantly enhanced the survival rate of <i>Galleria mellonella</i> larvae infected with <i>M. mycetomatis</i> at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like <b>14</b> and <b>18</b> with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.