Convenient Synthesis of N-Alkyl-2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetamides and Methyl-2-[2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetylamino]alkanoates

Samir Mohamed El Rayes; Gaber El-Enany; Mohamed Sayed Gomaa; Ibrahim A I Ali; Walid Fathalla; Faheem Hyder Pottoo; Firdos Alam Khan

doi:10.1021/acsomega.2c03522

Convenient Synthesis of N-Alkyl-2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetamides and Methyl-2-[2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetylamino]alkanoates

ACS Omega. 2022 Sep 15;7(38):34166-34176. doi: 10.1021/acsomega.2c03522. eCollection 2022 Sep 27.

Authors

Samir Mohamed El Rayes¹, Gaber El-Enany^{2

3}, Mohamed Sayed Gomaa⁴, Ibrahim A I Ali¹, Walid Fathalla³, Faheem Hyder Pottoo⁵, Firdos Alam Khan⁶

Affiliations

¹ Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
² Department of Physics, College of Science and Arts in Uglat Asugour, Qassim University, Buraydah 52571, Kingdom of Suadi Arabia.
³ Science & Math Department, Faculty of Engineering, Port Said University, Port Said 42526, Egypt.
⁴ Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.
⁵ Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.
⁶ Department of Stem Cell Research, Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.

Abstract

A series of 27 new quinoxaline derivatives (N-alkyl-[2-(3-phenyl-quinoxalin-2-ylsulfanyl)]acetamides, methyl-2-[2-(3-phenylquinoxalin-2-ylsulfanyl)-acetylamino]alkanoates, and their corresponding dipeptides) were prepared from 3-phenylquinoxaline-2(1H)-thione based on the chemoselective reaction with soft electrophiles. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to study the efficacy of 27 compounds on cancer cell viability and proliferation. A total of 13 compounds (4a-c, 5, 6, 8c, 9c, 9f, 10a, 10b, 11c, 12b, and 12c) showed inhibitory action on HCT-116 cancer cells and 15 compounds (4a-c, 5, 6, 8c, 9a, 9c, 9f, 9h, 10b, 11c, 12a, 12b, and 12c) showed activity on MCF-7 cancer cells, with compound 10b exhibiting the highest inhibitory action (IC₅₀ 1.52 and 2 μg/mL, respectively) on both cell lines. The molecular modeling studies on the human thymidylate synthase (hTS) homodimer interface showed that these compounds are good binders and could selectively inhibit the enzyme by stabilizing its inactive conformation. The study also identified key residues for homodimer binding, which could be used for further optimization and development.