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Synthesis, antiproliferative activity, and molecular modeling of novel 4-methylcoumarin derivatives and/or nitric oxide donor hybrids

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Abstract

Two new 4-methylcoumarin derivatives (3a–f and 4a–f) were designed, synthesized, and evaluated for their cytotoxic activity. Different spectroscopic methods and elemental analyses confirmed all the synthesized derivatives’ characterization. All the prepared compounds were biologically screened against four cancer cell lines (hepatocellular carcinoma HepG-2, colon cancer cell lines HCT-116, breast cancer cell lines MCF-7, and prostate cancer cell lines PC3). The in vitro antiproliferative activity of the target analogues 4b, 4c, 4f, 3b, and 3d against the MCF-7 cancer cell line was significant, with IC50 values of 3.98, 7.80, 10.94, 17.7, and 24.07 μM, respectively. Furthermore, the potent cytotoxic oxime derivative 4b was evaluated for cell cycle analysis showing a significant substantial disruption in cell cycle profile and cell cycle arrest at the S phase boundary with a time-dependent rise in a pre-G cell population, as well as a 22-fold increase in MCF-7 apoptosis compared to control cells. Accordingly, the Bax/Bcl-2 ratio, a critical ratio in controlling cell sensitivity to apoptosis, increased upon treatment with the oxime analog 4b. A docking investigation was conducted within the BcL-2 binding site to explore and anticipate the binding modes of the synthesized compounds. Thus, synthesizing these novel coumarin/nitric oxide hybrids may aid in developing promising antiproliferative agents.

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Acknowledgements

The authors would like to thank Nahda University, Beni-Suef, Egypt and Deraya University, Minia, Egypt, for their support.

Funding

The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research Grant No. (DSR-2021-01-0221).

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Authors and Affiliations

  1. Department of Pharmaceutics College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia

    Malik Suliman Mohamed & Omar Awad Alsaidan

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt

    Hany A. M. Elsherief

  3. Pharmaceutical Chemistry Branch, Pharmacy Department, Al-Esraa University College, Baghdad, Iraq

    Hani Mohamed Hafez

  4. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, Saudi Arabia

    Samil I. Alzarea

  5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni Suef, Egypt

    Asmaa M. AboulMagd

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  1. Malik Suliman Mohamed
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Contributions

Manuscript writing, AMA, HA, MS, OAA, SLA and HH; biological work, chemical work, HA, AMA, SLA, and HH; design and supervision, AMA, OAA, and HA. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Malik Suliman Mohamed or Asmaa M. AboulMagd.

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Mohamed, M.S., Elsherief, H.A.M., Hafez, H.M. et al. Synthesis, antiproliferative activity, and molecular modeling of novel 4-methylcoumarin derivatives and/or nitric oxide donor hybrids. Mol Divers 27, 2133–2146 (2023). https://doi.org/10.1007/s11030-022-10547-w

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