Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Design, synthesis and cytotoxic evaluation of 2-amino-4-aryl-6-substituted pyridine-3,5-dicarbonitrile derivatives

Amr S Abu Lila^1,2 , Marwa H Abdallah^1,2, El-Sayed Khafagy^3,4, Tamer M Shehata⁵, Mahmoud S Soliman^1,6, Kareem M Younes⁷, Mohamed Omran⁴, Shadeed Gad⁴

¹Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia; ²Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; ³Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia; ⁴Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 41552, Egypt; ⁵Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Alhofuf, Al-Ahsa 31982, Saudi Arabia; ⁶Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt; ⁷Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia.

For correspondence:- Amr Lila Email: a.abulila@uoh.edu.sa Tel:+966565434262

Accepted: 24 September 2021 Published: 31 October 2021

Citation: Lila AS, Abdallah MH, Khafagy E, Shehata TM, Soliman MS, Younes KM, et al. Design, synthesis and cytotoxic evaluation of 2-amino-4-aryl-6-substituted pyridine-3,5-dicarbonitrile derivatives. Trop J Pharm Res 2021; 20(10):2127-2133 doi: 10.4314/tjpr.v20i10.16

© 2021 The authors.
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Abstract

Purpose: To synthesize novel pyridine derivatives and evaluate their efficiency as potent inhibitors of cyclin dependent kinase 2 (CDK2) enzyme for cancer therapy.

Methods: Pyridine scaffold were synthesized using one-pot multicomponent condensation reaction of arylidine with different primary amines. The cytotoxic potential of the new compounds was assessed using various cell lines. Furthermore, molecular docking studies based on the crystal structure of CDK2 was carried out to determine the possible binding modes that influence the anticancer activities.

Results: The results indicate that one-pot multicomponent reaction generated a series of functionalized pyridines with good yield. In vitro cytotoxicity study revealed superior cytotoxicity of the designed compounds against prostate and cervical cancer cell lines compared to 5-fluorouracil (standard anticancer compound) with half-maximal inhibitory concentration (IC₅₀) values of 0.1 – 0.85 and 1.2 – 74.1 μM, respectively. Finally, molecular modeling simulation of the newly synthesized compounds showed that they fit well and are stabilized into CDK2 active site via hydrogen bonding and hydrophobic interactions.

Conclusion: The results indicate that the newly synthesized pyridine can exert potent anticancer activity presumably via inhibition of CDK2. However, this will need to be confirmed in in vivo studies.

Keywords: 5-Fluorouracil, Anticancer activity, Cyclin dependent kinase 2, Molecular docking, One-pot multicomponent reaction, Pyridine scaffold