02634nas a2200277   4500008004100000022001400041245014100055210006900196260000900265300001400274490000600288520167100294653002101965653002001986653002002006653001502026653002202041100002502063700002302088700002302111700002402134700002002158700001902178700002802197856013102225       2019                        eng d  a2365-654900aDesign and synthesis of 2-amino-thiophene-proline-conjugates and their anti-tubercular activity against mycobacterium tuberculosis H37Ra0 aDesign and synthesis of 2aminothiopheneprolineconjugates and the  cMAR   a2851-28570 v43 a<p>The emergence of extensively drug resistant tuberculosis (XDRTB) and multi-drug resistant tuberculosis (MDR-TB) has necessitated the development of new drugs with short chemotherapy treatment regime and cost effectiveness. To overcome these challenges, we are reporting the synthesis of a series of 2-amino-thiophene-proline-conjugates which show potent invino and ex-vivo anti-tubercular (anti-TB) activity against mycobacterium tuberculosis (rntb) H37Ra. The synthesis of these 2-amino-thiophene-proline-conjugates was carried out via solution phase peptide coupling reactions using methyl-2aminothiophene-3-carboxylate 8 as an intermediate obtained by modified gewald reaction. Intermediate 8 was coupled with different amino acids to obtain dipeptides 3, 4, 5, 6a and 7. Priliminary anti-TB assay data encoureaged us to synthesize modified proline derivatives 6b-6k via formation of a benzoxazinone intermediate 16. Most of these conjugates are active against mtb H37Ra in both active (A) and dormant (D) strains. They are also active against drug resistant mtb H37Ra strains. A trifluoroethyl ester analog, 6i was the most potent among the series [MIC 1 mu g/mL] along with 6f and 6g [MIC 2-6 mu g/mL]. Cytotoxicity studies suggested that, these compounds are less cytotoxic to human cell lines HeLa, MCF-7, HUVEC and hence possess high selectivity index (SI). Docking studies revealed that the binding mode of most active compounds 6i, 6g and 6f is in accordance with their bioactivity studies having docking score 8.969, 8.446 and 7.865, respectively. More- over, in sllico ADME properties suggest that all the compounds possess drug like properties.</p>
10a2-aminothiophene10aAnti-tubercular10adocking studies10aInh A gene10aselectivity index1 aBaravkar, Sachin, B.1 aWagh, Mahendra, A.1 aNawale, Laxman, U.1 aChoudhari, Amit, S.1 aBhansali, Sujit1 aSarkar, Dhiman1 aSanjayan, Gangadhar, J.  uhttp://library.ncl.res.in/content/design-and-synthesis-2-amino-thiophene-proline-conjugates-and-their-anti-tubercular-activity02593nas a2200349   4500008004100000022001400041245019200055210006900247260000900316300001100325490000800336520142000344653001501764653001001779653002001789653002001809653002101829653001701850100001801867700002001885700001801905700002101923700002401944700002301968700001901991700002202010700001602032700002402048700002402072700002102096856012602117       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<p>
	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 &amp; 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 &amp; 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.</p>
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  uhttp://library.ncl.res.in/content/synthesis-biological-evaluation-and-docking-studies-silicon-incorporated-diarylpyrroles