In this study, a series of 49 five-membered
heterocyclic compounds
containing either a pyridine- or a pyrrole-type nitrogen were synthesized
and tested against Mycobacterium tuberculosis. Among
them, only the 1,3,5-trisubstituted pyrazoles 5–49 exhibited minimum inhibitory concentration values in the
low micromolar range, and some also exhibited an improved physicochemical
profile without cytotoxic effects. Three pyrazoles were subjected
to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial
counts compared with untreated mice. Moreover, to determine the target
of this series, resistors were generated, and whole genome sequencing
revealed mutations in the mmpL3 gene.
The most interesting branch of research concerns the conjugation of a COX-inhibitor scaffold to a molecule able to modulate a different target, in order to either enhance anti-inflammatory activity or to act as a dual inhibitor. Among the described compounds, selenium-containing coxibs inhibiting COX-2 and Akt, in addition to the multi-target biphenyl derivatives as dual inhibitors of COX and fatty acid amide hydrolase, are the most promising ones.
MmpL3 belongs to the Resistance, Nodulation and Division (RND) superfamily whose role in mycobacteria is the formation of the outer membrane. Indeed, it has been shown that MmpL3 is associated with the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or the outer membrane. In the last few years several whole cell-based screenings of compound libraries brought by a number of diverse chemical scaffolds active against M. tuberculosis (Mtb) that surprisingly share MmpL3 as target. The diverse identified pharmacophores owe important differences among each other, in fact while some of them display inhibitory activity against pathogens that are devoid of mycolic acids and are active against non-replicating Mtb bacilli, some others specifically target mycobacteria and do not kill non-replicating bacilli. The scope of this review is to provide the recent advances in MmpL3 inhibitor discovery with a special focus on structure activity relationship (SAR) studies in order to provide information that could help in developing novel membrane-active anti- TB agents. Moreover, this review will provide the most recent insights into the modes of action of the MmpL3 inhibitors.
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