Efficient Protocol for Novel Hybrid Pyrimidines Synthesis: Antiproliferative Activity, DFT Analyses, and Molecular Docking Studies

Ibrahim O Althobaiti; Mjd Saleh Morezeq Alserhani; Wael A A Arafa; Amira A Ghoneim; Modather F Hussein; Hamada Mohamed Ibrahim; Asmaa K Mourad

doi:10.1021/acsomega.3c07434

Efficient Protocol for Novel Hybrid Pyrimidines Synthesis: Antiproliferative Activity, DFT Analyses, and Molecular Docking Studies

ACS Omega. 2023 Dec 1;8(49):47239-47253. doi: 10.1021/acsomega.3c07434. eCollection 2023 Dec 12.

Authors

Ibrahim O Althobaiti¹, Mjd Saleh Morezeq Alserhani², Wael A A Arafa^{2

3}, Amira A Ghoneim^{2

4}, Modather F Hussein^{2

5}, Hamada Mohamed Ibrahim³, Asmaa K Mourad³

Affiliations

¹ Chemistry Department, College of Science and Arts, Jouf University, Gurayat 77217, Saudi Arabia.
² Chemistry Department, College of Science, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
³ Chemistry Department, Faculty of Science, Fayoum University, P.O. Box 63514 Fayoum, Egypt.
⁴ Chemistry Department, Faculty of Science, Zagazig University, Zagazig 7120001, Egypt.
⁵ Chemistry Department, Faculty of Science, Al-Azhar University, Asyut 71524, Egypt.

Abstract

An efficient, microwave/ultrasound-irradiated synthesis of novel chromenopyrimidines has been established. 2-Amino-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (1) underwent cyclization reactions with various assorted reagents under sustainable conditions to afford a family of fused pyrimidine derivatives. The proposed structures of the designed fused pyrimidines were confirmed by several spectral techniques. Moreover, the targeted pyrimidines were estimated for their in vitro cytotoxic activities toward three carcinoma cell lines: breast (MCF7), hepatocyte (HepG2), and lung (A549) cancer cell lines, as well as one noncancerous cell line (MCF-10A). Structure-activity relationship (SAR) analyses revealed that derivatives 3 and 7 exhibited the highest potency in inhibiting the growth of cancer cells tested in vitro. Particularly, 3-amino-4-imino-5-(thiophen-2-yl)-3,4,5,7,8,9-hexahydro-6H-chromeno[2,3-d]pyrimidin-6-one (3) displayed a robust impact with IC₅₀ values ranging from 2.02 to 1.61 μM. Interestingly, compound 3 was observed to have low cytotoxicity toward noncancerous cell (MCF-10A) compared to the standard drug (Doxorubicin). Further, quantum chemical computations of the designed molecules utilizing density functional theory (DFT) were conducted and shown to be compatible with the observed antiproliferative properties. Thorough docking investigations revealed that the assembled compounds possess exceptionally low binding energies toward our three selected proteins: 4b3z-Lung, HepG2-2JW2, and 6ENV-MCV-7. Based on these intriguing results, compound 3 could be further evaluated for preclinical screening, potentially paving the way for its utilization as a promising cancer treatment.