Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma- to broad-spectrum antimycetomal drugs.

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 , 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 screening against two fungal strains of and three bacterial strains of and . Seven NIQs, mostly dimers, showed promising 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'''-,-dimethylmichellamine A (), inhibited all tested fungal and bacterial strains (IC = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (), inhibited a strain of and significantly enhanced the survival rate of larvae infected with at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like and with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.