Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against <i>Mycobacterium tuberculosis</i>
Dário Silva,
Márcio V. C. Lopes,
Željko Petrovski,
Miguel M. Santos,
Jussevania P. Santos,
Sueli F. Yamada-Ogatta,
Marcelle L. F. Bispo,
Marcus V. N. de Souza,
Ana Rita C. Duarte,
Maria C. S. Lourenço,
Raoni Schroeder B. Gonçalves,
Luis C. Branco
Affiliations
Dário Silva
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, 2829-516 Caparica, Portugal
Márcio V. C. Lopes
Instituto de Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, Cidade Universitaria, Rio de Janeiro 21941-909, Brazil
Željko Petrovski
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, 2829-516 Caparica, Portugal
Miguel M. Santos
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, 2829-516 Caparica, Portugal
Jussevania P. Santos
Departamento de Microbiologia, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina 86057-970, Brazil
Sueli F. Yamada-Ogatta
Departamento de Microbiologia, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina 86057-970, Brazil
Marcelle L. F. Bispo
Departamento de Microbiologia, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid (PR 445), Km 380, Campus Universitário, Londrina 86057-970, Brazil
Marcus V. N. de Souza
FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100, Manguinhos, Rio de Janeiro 21041-250, Brazil
Ana Rita C. Duarte
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, 2829-516 Caparica, Portugal
Maria C. S. Lourenço
Instituto de Pesquisas Clínica Evandro Chagas—IPEC, Av. Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, Brazil
Raoni Schroeder B. Gonçalves
Instituto de Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, Cidade Universitaria, Rio de Janeiro 21941-909, Brazil
Luis C. Branco
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, 2829-516 Caparica, Portugal
The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).
