SQ109 analogues with potent antimycobacterial activity

ALEJANDRO RECIO BALSELLS; GUILLERMO R. LABADIE; JUAN MANUEL BELARDINELLI; HÉCTOR R. MORBIDONI

Simposio; Tuberculosis: Science Aimed at Ending the Epidemic; 2020

Keystone Symposia

SQ109, a N,N´-disubstituted ethylendiamine, has shown a broad spectrum activity on Mycobacterium tuberculosis and parasites. Our group developed a library of N,N´-disubstituted aliphatic diamines (N,N´-Di) some of which displayed IC50 below 1 M against trypanosomatids (T. cruzi, L. donovani and T. brucei) and P. falciparum. Based on the common structural features of SQ109 and our N,N´-Di library, we explored the anti-mycobacterial activity of the compounds determining the minimum inhibitory concentration (MIC) against M. tuberculosis H37Rv (MTB). Ten compounds displayed MIC values below 10 M against MTB. To confirm the activity of these analogs, seven selected members of the collection were retested against MTB on solid medium with the most active analog displaying a MIC= 3.4 M. In order to explore their microbial selectivity the compounds were assayed on selected bacteria and fungi. The results, together with our previous results on parasites, showed that the activity of the compounds was higher on parasites followed by MTB and then other bacteria and fungi. This broad spectrum activity of the library could indicate that the N,N´-Di may have a similar mechanism of action than SQ109, involving the electron transport chain. This hypothesis will be analyzed in the future along with the possible involvement of the mycobacterial Mmpl3, an essential mycolate transporter.