02594nas a2200349 4500008004100000022001400041245019200055210006900247260000900316300001100325490000800336520142000344653001501764653001001779653002001789653002001809653002101829653001701850100001801867700002001885700001801905700002101923700002401944700002301968700001901991700002202010700001602032700002402048700002402072700002102096856012702117 2023 eng d a0223-523400aSynthesis, biological evaluation and docking studies of silicon incorporated diarylpyrroles as MmpL3 inhibitors: an effective strategy towards development of potent anti-tubercular agents0 aSynthesis biological evaluation and docking studies of silicon i cNOV  a1156330 v2593 a

Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 & mu;M, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 & mu;M against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.

10aantibiotic10aBM21210adocking studies10aMmpL3 inhibitor10aSilicon analogue10atuberculosis1 aVasudevan, N.1 aMotiwala, Zenia1 aRamesh, Remya1 aWagh, Sachin, B.1 aShingare, Rahul, D.1 aKatte, Revansiddha1 aAnand, Amitesh1 aChoudhary, Sushil1 aKumar, Ajay1 aGokhale, Rajesh, S.1 aKulkarni, Kiran, A.1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/synthesis-biological-evaluation-and-docking-studies-silicon-incorporated-diarylpyrroles