Synthesis and Evaluation of Some New 4 H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

Nahed N E El-Sayed; Magdi E A Zaki; Sami A Al-Hussain; Abir Ben Bacha; Malika Berredjem; Vijay H Masand; Zainab M Almarhoon; Hanaa S Omar

doi:10.3390/ph15070891

Synthesis and Evaluation of Some New 4 H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

Pharmaceuticals (Basel). 2022 Jul 19;15(7):891. doi: 10.3390/ph15070891.

Authors

Nahed N E El-Sayed¹, Magdi E A Zaki², Sami A Al-Hussain², Abir Ben Bacha^{3

4}, Malika Berredjem⁵, Vijay H Masand⁶, Zainab M Almarhoon⁷, Hanaa S Omar^{8

9}

Affiliations

¹ National Organization for Drug Control and Research, Egyptian Drug Authority (EDA), 51 Wezaret El-Zeraa St., Giza 35521, Egypt.
² Department of Chemistry, Faculty of Sciences, Imam Mohammad Ibn Saud Islamic University, Riyadh 13318, Saudi Arabia.
³ Biochemistry Department, College of Sciences, King Saud University, Riyadh 11495, Saudi Arabia.
⁴ Laboratory of Plant Biotechnology Applied to Crop Improvement, Faculty of Science of Sfax, University of Sfax, Sfax 3038, Tunisia.
⁵ Laboratory of Applied Organic Chemistry LCOA, Synthesis of Biomolecules and Molecular Modeling Group, Badji-Mokhtar-Annaba University, Annaba 23000, Algeria.
⁶ Department of Chemistry, Vidya Bharati College, Amravati 444602, Maharashtra, India.
⁷ Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
⁸ Department of Genetics, Faculty of Agriculture, Cairo University, Giza 12613, Egypt.
⁹ GMO Laboratory, Faculty of Agriculture, Cairo University, Research Park, Giza 12613, Egypt.

Abstract

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC₅₀ values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC₅₀ values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski's rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool.

Keywords: 4H-pyran; ADME; CDK2; caspases; colorectal cancer; dysbiosis; oxidative stress.

Grants and funding

Research group no-RG.21-09-76./The Deanship of Scientific Research at Imam Mohammad bin Saud Islamic University, Riyadh, Saudi Arabia