Discovery of Novel 1,2,3-Triazole Analogues as Anti-Tuberculosis agents Using 3D QSAR, Molecular Docking, and In Silico ADMET Screening

Document Type : Research Paper


1 Faculty of Science, Moulay Ismail University, Meknes, Morocco

2 EST, Moulay Ismail University, Meknes, Morocco


Heterocyclic moieties become more interesting for chemists, pharmacologists, microbiologists, and other researchers owing to its indomitable biological potential as anti-infective agents. Among heterocyclic compounds, there is 1,2,3‐triazole nucleus which is one of the most important and well‐known heterocycles. Triazole core is considered as essential structure in medicinal chemistry and is widely used to synthesize molecules with medical benefits. In this work, a set of triazole analogues were identified as anti-tubercular agents through a series of computer-aided drug design processes, including three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, molecular docking and ADMET study to determine properties of these new proposed drugs. The CoMFA and CoMSIA models employed for a training set of 25 compounds gives reliable values of Q2 (0.63 and 0.65 respectively) and R2 (0.85 and 0.71 respectively). These results indicate that the developed models possess good predictive ability. Based on the 3D-QSAR contours new molecules with high predicted activities were designed. Moreover, surflex-docking was applied to highlight the important interactions between the ligand and mycobacterium tuberculosis receptor, Therefore to confirm the stability of predicted molecules in the receptor. In silico ADMET results show good properties for these new anti-tubercular agents.


[1]       R.G. Ducati, A. Ruffino-Netto, L.A. Basso, D.S. Santos 101 (2006) 697.
[2]       R.C. Brito, C. Gounder, D.B. De, Lima, H. Siqueira, H.R. Cavalcanti, M.M. Pereira, A.L. Kritski, JBP. J. Brasileiro de Pneumologia 30 (2004) 425.
[3]       K. Roy, S. Kar, R.N. Das, A Primer on QSAR/QSPR Modeling, 2015.
[4]       H.G. Jeong, Y.W. Lee, Cancer Lett. 134 (1998) 73.
[5]       R.D. Cramer, D.E. Patterson, J.D. Bunce, JACS 110 (1988) 5959.
[6]       G. Klebe, U. Abraham, T. Mietzner, J. Med. Chem. 37 (1994) 4130.
[7]       M.H. Shaikh, D.D. Subhedar, L. Nawale, D. Sarkar, F.A. Kalam Khan, J.N. Sangshetti, B.B. Shingate, Med. Chem. Commun. 6 (2015) 1104.
[8]       M.O. St. Louis, SYBYL-X, version 2.0. Tripos Associates, USA, 2012.
[9]       Discovery Studio Visualizer, Accelrys Software, 2016.
[10]    D. Cao, J. Wang, R. Zhou, Y. Li, H. Yu, T. Hou, JCIM 52 (2012) 1132.
[11]    D.E.V. Pires, T.L. Blundell, D.B. Ascher, J. Med. Chem. 58 (2015) 4066.
[12]    M. Clark, R.D. Cramer, N. Van Opdenbosch, J. Comp. Chem. 10 (1989) 982.
[13]    W.P. Purcell, J.A. Singer, J. Chem. Eng. Data 12 (1967) 235.
[14]    M.D.M. Abdulhameed, A. Hamza, J. Liu, C.G. Zhan, J. Chem. Inf. Model 48 (2008) 1760.
[15]    A. Aouidate, A. Ghaleb, M. Ghamali, et al. J. Struct. Chem. 29 (2018) 1031.
[16]    L. Ståhle, S. Wold, Prog. Med. Chem. 25 (1988) 291.
[17]    B.L. Bush, R.B. Nachbar, J. Comput. Aided Mol. Des. 7 (1993) 587.
[18]    V.N. Viswanadhan, A.K. Ghose, G.R. Revankar, R.K. Robins, J. Chem. Inf. Comp. Sci. 29 (1989) 163.
[19]    S. Wold, Quant, Struct. Act. Relat. 10 (1991) 191.
[20]    M. Baroni, S. Clementi, G. Cruciani, G. Costantino, D. Riganelli, E. Oberrauch, J. Chemo. 6 (1992) 347.
[21]    C. Rücker, G. Rücker, M. Meringer, J. Chem. Inf. Model. 47 (2007) 2345.
[22]    W. Lin, K. Das, Y. Feng, R.H. Ebright, Mol. Cell. 66 (2017) 169.
[23]    A.N. Jain, J. Med. Chem. 46 (2003) 499.
[24]    J. Sun, S. Cai, H. Mei, J. Li, N. Yan, Y. Wang, J. Mol. Mod. 16 (2010) 1809.
[25]    S. Gharaghani, T. Khayamian, M. Ebrahimi, SAR QSAR Environ. Res. 24 (2013) 773.
[26]    Y. Ai, S.-T. Wang, P.-H. Sun, F.-J.  Song, Inter. J. Mol. Sci. 11 (2010) 3705.
[27]    P. Lan, W.N. Chen, W.M. Chen, Eur. J. Med. Chem. 46 (2011) 77.
[28]    P. Lan, W.N. Chen, G.K. Xiao, P.H. Sun, W.M. Chen, Bioorg. Med. Chem. Lett. 20 (2010) 6764.
[29]    G. Caldwell, Z. Yan, W. Tang, M. Dasgupta, B. Hasting, Curr. Top. Med. Chem. 9 (2009) 965.
[30]    H.E. Selick, A.P. Beresford, M.H. Tarbit, Drug Discov. Today 7 (2002) 109.
[31]    R. Gujjar, F. El Mazouni, K.L. White, J. White, S. Creason, D.M. Shackleford, P.K. Rathod, J. Med. Chem. 54 (2011) 3935.
[32]    C.A.  Lipinski,   F.   Lombardo,   B.W.   Dominy,   P.J.
Feeney, Adv. Drug Deliv. Rev. 46 (2001) 3.
[33]    D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple. J. Med. Chem. 45 (2002) 2615.
[34]    V.    Srimai,    M.    Ramesh,   K.S.   Parameshwar,   T.
Parthasarathy, Med. Chem. Res. 22 (2013) 5314.
[35]    R.K. Upadhyay, Bio. Med. Res. Inter. 2014 (2014) 37.
[36]    M.L. Amin, Drug Target Insights 2013 (2013) 27.
[37]    T. Lynch, A. Price, American Family Physician 76 (2007) 391.