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Quantitative structure–activity relationships (QSARs) and pharmacophore modeling for human African trypanosomiasis (HAT) activity of pyridyl benzamides and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides

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Abstract

In the present work, quantitative structure–activity relationship and pharmacophore modeling analysis were performed for human African trypanosomiasis healing activity of pyridyl benzamides (dataset-1) and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides (dataset-2). For quantitative structure–activity relationship analysis, a pool of descriptors (mono-dimensional to three-dimensional) was generated, followed by descriptor reduction using objective and subjective feature selection. Multiple splitting was employed for the generation of multiple quantitative structure–activity relationship models to get maximum information about the descriptors that have correlation with the HAT activity of pyridyl benzamides and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. The genetic algorithm-multilinear regression quantitative structure–activity relationship models have excellent statistical robustness with good external predictive ability. The pharmacophore model and quantitative structure–activity relationship analyses furnished complementary and consensus results to each other.

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References

  • Alafeefy AM, Alqasoumi SI, Ashour AE, Masand V, Al-Jaber NA, Ben Hadda T, Mohamed MA (2012) Quinazoline-tyrphostin as a new class of antitumor agents, molecular properties prediction, synthesis and biological testing. Eur J Med Chem 53:133–140

    Article  CAS  PubMed  Google Scholar 

  • Bandgar BP, Adsul LK, Chavan HV, Jalde SS, Shringare SN, Shaikh R, Meshram RJ, Gacche RN, Masand V (2012) Synthesis, biological evaluation, and docking studies of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines as potent anti-inflammatory and antioxidant agents. Bioorg Med Chem Lett 22(18):5839–5844

    Article  CAS  PubMed  Google Scholar 

  • Barakat A, Al-Najjar HJ, Al-Majid AM, Adil SF, Ali M, Masand VH, Ghabbour HA, Fun HK (2014) Synthesis, X-ray diffraction, thermogravimetric and DFT analyses of pyrimidine derivatives. Molecules 19(11):17187–17201

    Article  PubMed  Google Scholar 

  • Barrett MP, Vincent IM, Burchmore RJ, Kazibwe AJ, Matovu E (2011) Drug resistance in human African trypanosomiasis. Future Microbiol 6(9):1037–1047

    Article  PubMed  Google Scholar 

  • Bukhari SN, Jantan I, Masand VH, Mahajan DT, Sher M, Naeem-ul-Hassan M, Amjad MW (2014) Synthesis of alpha, beta-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid beta-induced cytotoxicity. Eur J Med Chem 83:355–365

    Article  CAS  PubMed  Google Scholar 

  • Bukhari SNA, Zhang X, Jantan I, Zhu HL, Amjad MW, Masand VH (2015) Synthesis, molecular modeling, and biological evaluation of novel 1, 3-diphenyl-2-propen-1-one based pyrazolines as anti-inflammatory agents. Chem Biol Drug Des 85(6):729–742

  • Carvalho AS, Salomao K, Castro SL, Conde TR, Zamith HP, Caffarena ER, Hall BS, Wilkinson SR, Boechat N (2014) Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme. Mem Inst Oswaldo Cruz 109(3):315–323

    Article  PubMed  PubMed Central  Google Scholar 

  • Chavan HV, Bandgar BP, Adsul LK, Dhakane VD, Bhale PS, Thakare VN, Masand V (2013) Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones. Bioorg Med Chem Lett 23(5):1315–1321

    Article  CAS  PubMed  Google Scholar 

  • Ebalunode JO, Zheng W, Tropsha A (2011) Application of QSAR and shape pharmacophore modeling approaches for targeted chemical library design. Methods Mol Biol 685:111–133

    Article  CAS  PubMed  Google Scholar 

  • Ferrins L, Rahmani R, Sykes ML, Jones AJ, Avery VM, Teston E, Almohaywi B, Yin J, Smith J, Hyland C, White KL, Ryan E, Campbell M, Charman SA, Kaiser M, Baell JB (2013) 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis. Eur J Med Chem 66:450–465

    Article  CAS  PubMed  Google Scholar 

  • Ferrins L, Gazdik M, Rahmani R, Varghese S, Sykes ML, Jones AJ, Avery VM, White KL, Ryan E, Charman SA, Kaiser M, Bergstrom CA, Baell JB (2014) Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei. J Med Chem 57(15):6393–6402

    Article  CAS  PubMed  Google Scholar 

  • Gilbert IH (2014) Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. Parasitology 141(1):28–36

    Article  PubMed  Google Scholar 

  • Gramatica P, Chirico N, Papa E, Cassani S, Kovarich S (2013) QSARINS: a new software for the development, analysis, and validation of QSAR MLR models. J Comput Chem 34:2121–2132

    Article  CAS  Google Scholar 

  • Gramatica P, Cassani S, Chirico N (2014) QSARINS-Chem: insubria datasets and new QSAR/QSPR models for environmental pollutants in QSARINS. J Comput Chem 35:1036–1044

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Fan X (2011) Why QSAR fails: an empirical evaluation using conventional computational approach. Mol Pharm 8(2):600–608

    Article  CAS  PubMed  Google Scholar 

  • Lutje V, Seixas J, Kennedy A (2013) Chemotherapy for second-stage human African trypanosomiasis. Cochrane Database Syst Rev 6:CD006201

    PubMed  Google Scholar 

  • Mahajan DT, Masand VH, Patil KN, Ben Hadda T, Jawarkar RD, Thakur SD, Rastija V (2012) CoMSIA and POM analyses of anti-malarial activity of synthetic prodiginines. Bioorg Med Chem Lett 22(14):4827–4835

    Article  CAS  PubMed  Google Scholar 

  • Masand VH, Mahajan DT, Patil KN, Hadda TB, Youssoufi MH, Jawarkar RD, Shibi IG (2013) Optimization of antimalarial activity of synthetic prodiginines: QSAR, GUSAR, and CoMFA analyses. Chem Biol Drug Des 81(4):527–536

    Article  CAS  PubMed  Google Scholar 

  • Masand VH, Mahajan DT, Gramatica P, Barlow J (2014a) Tautomerism and multiple modelling enhance the efficacy of QSAR: antimalarial activity of phosphoramidate and phosphorothioamidate analogues of amiprophos methyl. Med Chem Res 23(11):4825–4835

  • Masand VH, Mahajan DT, Hadda TB, Jawarkar RD, Alafeefy AM, Rastija V, Ali MA (2014b) Does tautomerism influence the outcome of QSAR modeling? Med Chem Res 23(4):1742–1757

  • Masand VH, Toropov AA, Toropova AP, Mahajan DT (2014c) QSAR models for anti-malarial activity of 4-aminoquinolines. Curr Comput Aided Drug Des 10(1):75–82

    Article  CAS  PubMed  Google Scholar 

  • Masand VH, Mahajan DT, Nazeruddin GM, Ben Hadda T, Rastija V, Alfeefy AM (2015) Effect of information leakage and method of splitting (rational and random) on external predictive ability and behavior of different statistical parameters of QSAR model. Med Chem Res 24:1241–1264

    Article  CAS  Google Scholar 

  • Nagle AS, Khare S, Kumar AB, Supek F, Buchynskyy A, Mathison CJN, Chennamaneni NK, Pendem N, Buckner FS, Gelb MH, Molteni V (2014) Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Chem Rev 114(22):11305–11347

  • Patil VM, Gupta SP, Samanta S, Masand N (2012) 3D-QSAR and docking studies on a series of benzothiadiazine derivatives as genotype 1 HCV polymerase inhibitors. Med Chem 8(6):1099–1107

    CAS  PubMed  Google Scholar 

  • Pourbasheer E, Shokouhi Tabar S, Masand VH, Aalizadeh R, Ganjali MR (2015) 3D-QSAR and docking studies on adenosine A receptor antagonists by the CoMFA method. SAR QSAR Environ Res 26 (6): 461-477

  • Rastija V, Nikolic S, Masand VH (2013) Quantitative relationships between structure and lipophilicity of naturally occurring polyphenols. Acta Chim Slov 60(4):781–789

    CAS  PubMed  Google Scholar 

  • Rastija V, Masand VH (2014) QSAR of antitrypanosomal activities of polyphenols and their analogues using multiple linear regression and artificial neural networks. Comb Chem High Throughput Screen 17(8):709–717

    Article  CAS  PubMed  Google Scholar 

  • Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J (2012) Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology 139(7):842–846

    Article  CAS  PubMed  Google Scholar 

  • Sykes ML, Baell JB, Kaiser M, Chatelain E, Moawad SR, Ganame D, Ioset JR, Avery VM (2012) Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign. PLoS Negl Trop Dis 6(11):e1896

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang J, Yan H, Wang G, Zhang X, Wang T, Gong X (2014) Computational investigations into the substituent effects of -N(3), -NF(2), -NO(2), and -NH(2) on the structure, sensitivity and detonation properties of N, N’-azobis(1,2,4-triazole). J Molec Model 20(4):2148

    Article  Google Scholar 

  • Yoon YK, Ali MA, Wei AC, Choon TS, Khaw KY, Murugaiyah V, Osman H, Masand VH (2013) Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors. Bioorg Chem 49:33–39

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are thankful to TINKER, ChemSketch 12 Freeware (ACD labs), and PaDEL developers for providing the free versions of their softwares. Authors are thankful to Dr. Paola Gramatica, Italy and her team for providing QSARINS-Chem (www.qsar.it).

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Authors and Affiliations

  1. Department of Chemistry, Vidya Bharati College, Camp, Amravati, Maharashtra, India

    Vijay H. Masand & Devidas T. Mahajan

  2. Department of Chemistry, Arts, Commerce and Science College, Narsamma Campus, Kiran Nagar, Amravati, Maharashtra, India

    Atish K. Maldhure

  3. Department of Chemistry, Faculty of Agriculture, Josip Juraj Strossmayer University of P. Svacica 1d, Osijek, Croatia

    Vesna Rastija

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  1. Vijay H. Masand
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  2. Devidas T. Mahajan
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  3. Atish K. Maldhure
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  4. Vesna Rastija
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Correspondence to Vijay H. Masand.

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Masand, V.H., Mahajan, D.T., Maldhure, A.K. et al. Quantitative structure–activity relationships (QSARs) and pharmacophore modeling for human African trypanosomiasis (HAT) activity of pyridyl benzamides and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Med Chem Res 25, 2324–2334 (2016). https://doi.org/10.1007/s00044-016-1664-1

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