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Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening

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Abstract

Novel pyrrolo[2,3-d]pyrimidine-based analogues were designed, synthesized, and evaluated for their ability to inhibit the α-amylase enzyme in order to treat diabetes. In vitro antidiabetic analysis demonstrated excellent antidiabetic action for compounds 5b, 6c, 7a, and 7b, with IC50 values in the 0.252–0.281 mM range. At a 200 μg/mL concentration, the exceptional percent inhibition values for compounds 5a, 5b, 5d, and 6a varied from 97.79 ± 2.86% to 85.56 ± 4.13% overperforming the standard (acarbose). Molecular docking of all compounds performed with Bacillus paralicheniformis α-amylase enzyme. The most active compounds via in vitro and non-toxic via in silico ADMET and molecular docking analysis, hybrids 6c, 7a, and 7b displayed binding affinity from − 8.2 and − 8.5 kcal/mol. Molecular dynamic simulations of most active compound 5b and 7a investigated into the active sites of the Bacillus paralicheniformis α-amylase enzyme for a 100-ns indicating the stability of hybrid-protein complex. Consistent RGyr values for the two complexes under study further suggest that the system's proteins are closely packed in the dynamic state. Synthesized analogs’ in vitro biological assessments, ADMET, molecular docking, and MD modelling reveal that 5b, 6c, 7a, and 7b hybrid analogs may be employed in the development of future antidiabetic drugs.

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Acknowledgements

The authors thank CUG, Gujarat, India, for providing spectral data. The authors are thankful to the Department of Chemistry of S.V. National Institute Technology, Surat, Gujarat, India, for providing all the facilities for the research work.

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Authors and Affiliations

  1. Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat, Gujarat, 395007, India

    Ajayrajsinh R. Zala, Ramgopal Tiwari, Hem N. Naik, Smita Jauhari & Premlata Kumari

  2. Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule, Maharashtra, 424002, India

    Iqrar Ahmad

  3. Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, 425405, India

    Harun Patel

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Contributions

ARZ: Conceptualization, methodology, writing original draft, and visualization. RGT: methodology and visualization. HNN: biological evaluation. AI: molecular dynamic simulation. HP, SJ, PK: supervision, writing review and editing. All authors reviewed the manuscript.

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Correspondence to Premlata Kumari.

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Zala, A.R., Tiwari, R., Naik, H.N. et al. Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10683-x

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