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Multiple 3D- and 2D-quantitative structure–activity relationship models (QSAR), theoretical study and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against tuberculosis

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Abstract

Tuberculosis (TB), an infectious remains a global health burden till date. Considering immense importance of theoretical tools in computer aided-drug designing, the current study focuses on common pharmacophore and QSAR analysis of 38 imidazopyridine analogues as anti-TB agents. Our developed atom-based, field-based, and multilinear regression based-QSAR models showed high values for statistical robustness for internal as well as external validations (a correlation coefficient: R2 > 0.9, least standard deviations, higher Fischer coefficient, and cross-validation correlation coefficient: Q2 > 0.5). From our ZINC-Drug-like analysis, we were retained with 5 hits (VS1-VS-5), among them VS-4 molecule was found to have high potency (predicted pIC50 (μM) value: 7.96 (against MTB H37Rv ATCC 27,294)) with good theoretical properties (high softness, and low hardness values). From our designed analogues (S1-S10), analogue S-10 was retained with high potency as well as good pharmacokinetics to act as good anti-mycobacterial agent in future.

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Data availability statement

Data will be made available upon reasonable request.

Abbreviations

TB:

Tuberculosis

QSAR model:

Quantitative structure–activity relationship model

DFT:

Density functional theory

MDR-TB:

Multi-drug-resistant tuberculosis

XDR-TB:

Extensively drug-resistant tuberculosis

3D-QSAR model:

3D-quantitative structure–activity relationship models

CPH:

Common pharmacophore hypothesis

R 2 :

Correlation coefficient

Q 2 :

Cross-validation correlation coefficient

RMSE:

Root mean square error

ADMET:

Absorption, distribution, metabolism, excretion and toxicity properties

MIC:

Minimum inhibitory concentration

IC50 :

Inhibitory concentration

PLS:

Partial least squares

References

  1. Mali SN, Chaudhari HK (2018) Computational studies on imidazo [1, 2-a] pyridine-3-carboxamide analogues as antimycobacterial agents: Common pharmacophore generation, atom-based 3D-QSAR, molecular dynamics simulation, QikProp, molecular docking and prime MMGBSA approaches. Open Pharm Sci J 5(1). https://doi.org/10.2174/1874844901805010012

  2. Tuberculosis - WHO (World Health Organization) Factsheet, Accessed online on: 21-01-2022. https://www.who.int/news-room/fact-sheets/detail/tuberculosis#

  3. Alemu MA, Yesuf A, Girma F, Adugna F, Melak K, Biru M, Seyoum M, Abiye T (2021) Impact of HIV-AIDS on tuberculosis treatment outcome in Southern Ethiopia–a retrospective cohort study. J Clin Tuberc Other Mycobact Dis 25:100279

  4. Lv K, Li L, Wang B et al (2017) Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine-3-carboxamide derivatives. Eur J Med Chem 137:117–125

    Article  CAS  Google Scholar 

  5. Khatun S, Singh A, Bader GN, Sofi FA (2021) Imidazopyridine, a promising scaffold with potential medicinal applications and structural activity relationship (SAR): recent advances. J Biomol Struct Dyn 1–24

  6. Kshatriya R, Kambale D, Mali S, Jejurkar VP, Lokhande P, Chaudhari HK, Saha SS (2019) Brønsted acid catalyzed domino synthesis of functionalized 4H-chromens and their ADMET, molecular docking and antibacterial studies. ChemistrySelect 4(27):7943–7948. https://doi.org/10.1002/slct.201901775

    Article  CAS  Google Scholar 

  7. Jejurkar VP, Mali SN, Kshatriya R, Chaudhari HK, Saha S (2019) Synthesis, antimicrobial screening and in silico appraisal of iminocarbazole derivatives. ChemistrySelect 4(32):9470–9475. https://doi.org/10.1002/slct.201901890

    Article  CAS  Google Scholar 

  8. Jadhav BS, Yamgar RS, Kenny RS, Mali SN, Chaudhari HK, Mandewale MC (2020) Synthesis, in silico and biological studies of thiazolyl-2h-chromen-2-one derivatives as potent antitubercular agents. Curr Comput Aided Drug Des 16(5):511–522. https://doi.org/10.2174/1386207322666190722162100

    Article  CAS  PubMed  Google Scholar 

  9. Desale VJ, Mali SN, Chaudhari HK, Thorat BR, Yamgar RS (2020) Synthesis and Anti-mycobacterium Study on Halo-substituted 2-aryl oxyacetohydrazones. Curr Comput Aided Drug Des 16(5):618–628. https://doi.org/10.2174/1573409915666191018120611

    Article  CAS  PubMed  Google Scholar 

  10. Anuse DG, Mali SN, Thorat BR, Yamgar RS, Chaudhari HK (2020) Synthesis, SAR, In silico appraisal and anti-microbial study of substituted 2-aminobenzothiazoles derivatives. Curr Comput Aided Drug Des 16(6):802–813. https://doi.org/10.2174/1573409915666191210125647

    Article  CAS  PubMed  Google Scholar 

  11. Thorat BR, Rani D, Yamgar RS, Mali SN (2020) Synthesis, spectroscopic, in-vitro and computational analysis of hydrazones as potential antituberculosis agents:(part-I). Comb Chem High Throughput Screening 23(5):392–401. https://doi.org/10.2174/1386207323999200325125858

    Article  CAS  Google Scholar 

  12. Leão RP, Cruz JV, da Costa GV, Cruz JN, Ferreira EFB, Silva RC, de Lima LR, Borges RS, dos Santos GB, Santos CBR (2020) Identification of new rofecoxib-based cyclooxygenase-2 inhibitors: a bioinformatics approach. Pharmaceuticals 13:209. https://doi.org/10.3390/ph13090209

    Article  CAS  PubMed Central  Google Scholar 

  13. Santana de Oliveira M, da Cruz JN, Almeida da Costa W, Silva SG, Brito MdP, de Menezes SAF, de Jesus Chaves Neto AM, de Aguiar Andrade EH, de Carvalho Junior RN (2020) Chemical Composition, Antimicrobial Properties of Siparuna guianensis Essential Oil and a Molecular Docking and Dynamics Molecular Study of its Major Chemical Constituent. Molecules 25(17):3852. https://doi.org/10.3390/molecules25173852

  14. Araújo PHF, Ramos RS, da Cruz JN, Silva SG, Ferreira EFB, de Lima LR, Macêdo WJC, Espejo-Román JM, Campos JM, Santos CBR (2020) Identification of potential COX-2 inhibitors for the treatment of inflammatory diseases using molecular modeling approaches. Molecules 25(18):4183. https://doi.org/10.3390/molecules25184183

    Article  CAS  PubMed Central  Google Scholar 

  15. Neto RDAM, Santos CBR, Henriques SVC, Machado LDO, Cruz JN, da Silva CHTP, Federico LB, de Oliveira EHC, de Souza MPC, da Silva PNB, Taft CA, Ferreira IM, Gomes MRF (2020) Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations. J Biomol Struct Dyn https://doi.org/10.1080/07391102.2020.1839562

  16. Santana de Oliveira M, Pereira da Silva VM, Cantão Freitas L, Gomes Silva S, Nevez Cruz J, de Aguiar Andrade EH (2021) Extraction yield, chemical composition, preliminary toxicity of Bignonia nocturna (Bignoniaceae) essential oil and in silico evaluation of the interaction. Chem Biodivers 18(4):e2000982

  17. Costa EB, Silva RC, Espejo-Román JM, de A. Neto MF, Cruz JN, Leite FHA, Silva CHTP, Pinheiro JC,  Macêdo WJC, Santos CBR (2020) Chemometric methods in antimalarial drug design from 1,2,4,5-tetraoxanes analogues, SAR and QSAR in Environmental Research 31(9):677-695. https://doi.org/10.1080/1062936X.2020.1803961

  18. Mali SN, Pandey A (2021) Molecular modeling studies on 2, 4-disubstituted imidazopyridines as anti-malarials: atom-based 3D-QSAR, molecular docking, virtual screening, in-silico ADMET and theoretical analysis. Journal of Computational Biophysics and Chemistry 20(03):267–282. https://doi.org/10.1142/S2737416521500125

    Article  CAS  Google Scholar 

  19. Mishra VR, Ghanavatkar CW, Mali SN, Qureshi SI, Chaudhari HK, Sekar N (2019) Design, synthesis, antimicrobial activity and computational studies of novel azo linked substituted benzimidazole, benzoxazole and benzothiazole derivatives. Comput Biol Chem 78:330–337

    Article  CAS  Google Scholar 

  20. Mali SN, Pandey A (2021) Balanced QSAR and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against trypanosomiases. J Comput Biophys Chem 1–32. https://doi.org/10.1142/S2737416521410015

  21. Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y (2012) admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties

  22. Yap CW (2011) PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints. J Comput Chem 32(7):1466–1474

    Article  CAS  Google Scholar 

  23. 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

  24. Chirico N, Sangion A, Gramatica P, Bertato L, Casartelli I, Papa E (2021) QSARINS‐Chem standalone version: A new platform‐independent software to profile chemicals for physico‐chemical properties, fate, and toxicity. J Comput Chem

  25. Raj KK, Manohar S, Talluri VR, Rawat DS (2015) Insights into activity enhancement of 4-aminoquinoline-based hybrids using atom-based and field-based QSAR studies. Med Chem Res 24(3):1136–1154

    Article  Google Scholar 

  26. Zhang G, Chen Y, Liu F, Huang J, Li P, Wang B, Zhao W, Chen M, Xu S, Guan F, Tian M (2021) Comprehensive investigation of structural properties (X-ray diffraction, IR, Hirshfeld, MEP and FMOs) and in silico screening of potential biological activity of Euphorbia factor L1. J Mol Struct 1246:131237

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Acknowledgements

We, the author(s) clearly indicate that some of explanations for theoretical section of this manuscript (data) has been presented previously in the conference proceeding (Section 3 (subsection 3.5 (Paragraph nos. 2–4) which can be accessed at https://sciforum.net/paper/view/11655 (13 November 2021 by MDPI in The 25th International Electronic Conference on Synthetic Organic Chemistry session Computational Chemistry).

We wish to thank the Dept. of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, India, for financial assistance and Schrodinger team, Banglore, India, for providing the technical and software support to carry out the work (a trial license provided to SM). Author is also thankful for the provision of IRF (PHD/PH/10006/20) (Ref. No. GO/Estb/Ph.D./IRF/2020–21/) provided by BIT, Mesra, India, to S.M. One of the authors SM is thankful to Dr. Paola Gramatica for providing the software QSARINS-Chem 2.2.1

Funding

Financial assistance provided by Dept. of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, India.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, India

    Suraj N. Mali & Anima Pandey

  2. Department of Chemistry, Government College of Arts and Science, 431 001, Aurangabad (M.S.), India

    Bapu R. Thorat

  3. Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, 40241, Taiwan

    Chin-Hung Lai

Authors
  1. Suraj N. Mali
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  2. Anima Pandey
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  3. Bapu R. Thorat
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  4. Chin-Hung Lai
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Contributions

All the authors read and approved the final manuscript. SM and AP: writing, designing, visualization; BT: designing and software; CL: software and interpretations.

Corresponding author

Correspondence to Suraj N. Mali.

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Mali, S.N., Pandey, A., Thorat, B.R. et al. Multiple 3D- and 2D-quantitative structure–activity relationship models (QSAR), theoretical study and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against tuberculosis. Struct Chem 33, 679–694 (2022). https://doi.org/10.1007/s11224-022-01879-2

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