Avaliação do potencial antimicobacteriano e toxicidade de compostos análogos a cloroquina e ao etambutol

Abstract

Mycobacterium tuberculosis is the causative microorganism of tuberculosis, an infectious and contagious chronic disease that, if not adequately treated, can lead to the death of the affected individual. The emergence of resistant strains of MTB, which do not respond to conventional treatments, represents a serious concern for health authorities. As a result, it is necessary to develop new pharmacological alternatives with anti-tuberculous potential. In this sense, the present work aimed to evaluate the antimycobacterial activity and toxicity of five analogous compounds simultaneously to chloroquine and ethambutol. To this end, these analogues were tested against MTB H37Ra to determine their minimum inhibitory concentration, in addition to having their cytotoxicity evaluated in Vero E6 and RAW 264.7 cell lines. The toxicity of the analogues was also evaluated based on their exposure to Artemia salina. Carrying out these tests allowed us to conclude that the DOC-79, DOC-89, DOC-107 and DOC-120 molecules showed antimycobacterial activity of 25 µg/mL, while DOC-76 showed 12.5 µg/mL. The DOCs did not compromise the viability of the Vero E6 strain, but the viability of RAW 264.7 was compromised at all concentrations tested. Exposure to treatment with DOCs did not compromise the survival of A. salina at concentrations corresponding to their MICs. From this experiment, DOC-76 was the analogue chosen as the lead molecule due to its antimicrobial capacity and relative pharmacological safety. The combination between DOC-76 and rifampicin resulted in additive activity, while the combinations with ethambutol and moxifloxacin resulted in no interaction. The inhibitory potential against MTB, its pharmacological safety profile and the absence of antagonistic activity against the drugs tested suggest that DOC-76 can be considered a promising candidate for future trials aiming to incorporate new alternatives for the treatment of tuberculosis.