Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria

Abstract

A series of N-phenyl-2,5-dimethylpyrrole derivatives, designed as hybrids of the antitubercular agents BM212 and SQ109, have been synthesized and evaluated against susceptible and drug-resistant mycobacteria strains. Compound 5d, bearing a cyclohexylmethylene side chain, showed high potency against M. tuberculosis including MDR-TB strains at submicromolar concentrations. The new compound shows bacteriostatic activity and low toxicity and proved to be effective against intracellular mycobacteria too, showing an activity profile similar to isoniazid.

Figure 1

Pyrrole hybrid derivatives 1 and 2 and the rational approach of the proposed work.

Scheme 1. Synthesis of Antimycobacterial Derivatives 5, 7, 9, and 11

Figure 2

Time-kill of MTB H37Rv according to time (days) in the presence of 5d (0.32 μg/mL) or moxifloxacin (MOX – 0.07 μg/mL) or untreated (growth control).

Figure 3

(a) Percent inhibition of intramacrophage MTB (Cell line J774A.1, murine origin) in the presence of 5d, moxifloxacin (MOX), or isoniazid (INH). Concentrations: 5d (1 x MIC = 0.32 μg/mL; 5 x MIC = 1.6 μg/mL, and 10 x MIC = 3.2 μg/mL); INH (1 x MIC = 0.06 μg/mL; 5 x MIC = 0.30 μg/mL, and 10 x MIC = 0.60 μg/mL); MOX (1 x MIC = 0.07 μg/mL; 5 x MIC = 0.35 μg/mL, and 10 x MIC = 0.70 μg/mL). The results are the mean and standard error of experiments performed in duplicate. * = Statistically different from the untreated control (P < 0.05) by GraphPad Prism (One-way ANOVA with Dunnett’s Multiple Comparison Post Test). (b) Intracellular activity of 5d via HT-SPOTi assay.

Figure 4

Binding of 5d (top left), 5a (bottom left), BM212 (top right), and SQ109 (bottom right) with the M. tuberculosis MmpL3 homology model.

Figure 5

Binding interactions of pyrroles 5a, 5d, 5i, and 5l.