Mefloquine–oxazolidine derivatives, derived from mefloquine and arenecarbaldehydes: In vitro activity including against the multidrug-resistant tuberculosis strain T113

Abstract

Ten new mefloquine-oxazolidine derivatives, 4-[(1S,8aR)-3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (1: aryl=substituted phenyl) and 4-[(1S,8aR)-3-(heteroaryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline [2: heteroaryl=5-nitrothien-2-yl (2a); 5-nitrofuran-2-yl (2b) and 4H-imidazol-2-yl) (2c)], have been synthesized and evaluated against Mycobacterium tuberculosis. Compounds 1f (aryl=3-ethoxyphenyl), 1g (Ar=3,4,5-(MeO)(3)-C(6)H(2)) and 2c were slightly more active than mefloquine (MIC=33μM) with MICs=24.5, 22.5 and 27.4, respectively, whereas compounds 1e (aryl=3,4-(MeO)(2)-C(6)H(3)) and 2a (MICs=11.9 and 12.1μM, respectively) were ca. 2.7 times more active than mefloquine, with a better tuberculostatic activity than the first line tuberculostatic agent ethambutol (MIC=15.9). The compounds were also assayed against the MDR strain T113 and the same MICs were observed. Thus the new derivatives have advantages over such anti-TB drugs as isoniazid, rifampicin, ethambutol and ofloxacin, for which this strain is resistant. The most active compounds were not cytotoxic to Murine Macrophages Cells in a concentration near their MIC values.

Mefloquine as a potential drug against multidrug-resistant tuberculosis

“…GONÇALVES et al [4] showed that mefloquine-oxazolidine derivates have in vitro activity against M. tuberculosis. In addition, mefloquine can inhibit the Mycobacteria species in a MIC range of 8-16 µg·mL…”

Quinoline and quinolones: promising scaffolds for future antimycobacterial agents

“…The study showed that the electronic nature of substituents in the aryl ring plays a significant role on the antimycobacterial activity. Inhibitors having electronreleasing groups, such as hydroxy and methoxy groups, were more active than electron-withdrawing chloro or nitro groups 31,33 . Eswaran et al designed four new series of hydrazine-linkedquinolines based on the structure of mefloquine (Figure 8).…”

Crystal structures of mefloquine-oxazolidine derivatives, 4-[3-(halophenyl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]- 2,8-bis(trifluoromethyl)quinolines

“…Moreover, several mefloquine derivatives have been reported to display modest to excellent actives against tuberculosis [14][15][16][17][18][19]. Among these derivatives is a series of mefloquine-oxazolidine derivatives, 2, [18,19], see Fig.…”

“…1. Certain of these derivatives, 2, especially those with electron releasing substituents, such as hydroxyl and alkoxyl groups, showed significant activity in in-vitro tests against the multidrug-resistant tuberculosis strain T113 [19]. However as (2: X ¼ H) and (2: X ¼ 4-F) also had reasonable activities as anti-TB agents, but not (2: X ¼ 2-F), (2: X ¼ 4-Cl) nor (2: X ¼ 4-Br), the activity data suggested that factors, other than the electronic effects of substituents, could also be important.…”

“…The crystal structures of (2: X ¼ H, 2-NO 2 , 3-NO 2 , 4-NO 2 ) [20], 2-OH [21], 4-OH, 3-OMe and 4-OMe) [22] and 3 [19] have been reported. From the structural data for these compounds, there was no clear indication that the solid state conformation was a factor influencing biological activity.…”