In Silico and In Vitro Studies of 4-Hydroxycoumarin-Based Heterocyclic Enamines as Potential Anti-Tumor Agents

Mediha Assad; Rizwan Nasir Paracha; Abu Bakar Siddique; Muhammad Ashraf Shaheen; Nadeem Ahmad; Muhammad Mustaqeem; Fariha Kanwal; Muhammad Zia Ul Mustafa; Muhammad Fayyaz Ur Rehman; Sumaya Fatima; Changrui Lu

doi:10.3390/molecules28155828

In Silico and In Vitro Studies of 4-Hydroxycoumarin-Based Heterocyclic Enamines as Potential Anti-Tumor Agents

Molecules. 2023 Aug 2;28(15):5828. doi: 10.3390/molecules28155828.

Authors

Affiliations

¹ College of Biological Sciences and Medical Engineering, Donghua University, 2999 North Ren Min Road, Shanghai 201620, China.
² Department of Chemistry, Government Graduate Islamia College for Women Cantt Lahore, Lahore 54000, Pakistan.
³ Department of Chemistry, Thal University Bhakkar, Bhakkar 30000, Pakistan.
⁴ Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan.
⁵ Department of Pharmacy, Comsats University Islamabad, Lahore Campus, Lahore 54000, Pakistan.
⁶ School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai 200030, China.
⁷ Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.

Abstract

The present study reports the one-step synthesis of several 3-formyl-4-hydroxycouramin-derived enamines (4a-4i) in good yields (65-94%). The characterization of the synthesized compounds was carried out via advanced analytical and spectroscopic techniques, such as melting point, electron impact mass spectrometry (EI-MS), ¹H-NMR, ¹³C-NMR, elemental analysis, FTIR, and UV-Visible spectroscopy. The reaction conditions were optimized, and the maximum yield was obtained at 3-4 h of reflux of the reactants, using 2-butanol as a solvent. The potato disc tumor assay was used to assess Agrobacterium tumefaciens-induced tumors to evaluate the anti-tumor activities of compounds (4a-4i), using Vinblastine as a standard drug. The compound 4g showed the lowest IC₅₀ value (1.12 ± 0.2), which is even better than standard Vinblastine (IC₅₀ 7.5 ± 0.6). For further insight into their drug actions, an in silico docking of the compounds was also carried out against the CDK-8 protein. The binding energy values of compounds were found to agree with the experimental results. The compounds 4g and 4h showed the best affinities toward protein, with a binding energy value of -6.8 kcal/mol.

Keywords: anti-tumor; coumarin; enamines; hydroxycoumarin.

MeSH terms

4-Hydroxycoumarins*
Antineoplastic Agents* / chemistry
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Vinblastine

Substances

Vinblastine
Antineoplastic Agents
4-Hydroxycoumarins

Grants and funding

Funding in the C.L. lab was provided by the Fundamental Research Funds for the Central Universities (2232021G-04), Shanghai Science and Technology Committee (19ZR1471100). The authors are also thankful for the online utilization of computational resources at C.L. lab, Donghua University, China.