Thieno[2,3- b]thiophene Derivatives as Potential EGFRWT and EGFRT790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies

Sanaa A Ahmed; Moumen S Kamel; Moustafa O Aboelez; Xiang Ma; Ahmed A Al-Karmalawy; Sayed A S Mousa; Elders Kh Shokr; H Abdel-Ghany; Amany Belal; Mohamed A El Hamd; Zafer S Al Shehri; Mahmoud Abd El Aleem Ali Ali El-Remaily

doi:10.1021/acsomega.2c06219

Thieno[2,3- b]thiophene Derivatives as Potential EGFR^WT and EGFRT^790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies

ACS Omega. 2022 Dec 3;7(49):45535-45544. doi: 10.1021/acsomega.2c06219. eCollection 2022 Dec 13.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Sohag University, Sohag82524, Egypt.
² Department of Chemistry, Faculty of Science, Sohag University, Sohag82524, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, Sohag82524, Egypt.
⁴ School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan430030, China.
⁵ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza12566, Egypt.
⁶ Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut Branch, Assiut71524, Egypt.
⁷ Department of Physics, Faculty of Science, Sohag University, Sohag82524, Egypt.
⁸ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef62514, Egypt.
⁹ Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif21944, Saudi Arabia.
¹⁰ Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra11961, Saudi Arabia.
¹¹ Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena83523, Egypt.
¹² Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra11961, Saudi Arabia.

Abstract

Microwave-assisted synthesis and spectral analysis of certain novel derivatives of 3,4-diaminothieno[2,3-b]thiophene-2,5-dicarbonitrile 1-7 were carried out. Compounds 1-7 were examined for cytotoxicity against MCF-7 and A549 cell lines using the quantitative MTT method, and gefitinib and erlotinib were used as reference standards. Compounds 1-7 were shown to be more active than erlotinib against the two cell lines tested. Compound 2 outperformed regular erlotinib by 4.42- and 4.12-fold in MCF-7 and A549 cells, respectively. The most cytotoxic compounds were subsequently studied for their suppression of kinase activity using the homogeneous time-resolved fluorescence assay versus epidermal growth factor receptor (EGFR^WT) and EGFR^790M. With IC₅₀ values of 0.28 ± 0.03 and 5.02 ± 0.19, compound 2 was demonstrated to be the most effective against both forms of EGFR. Furthermore, compound 2 also had the best antioxidant property, decreasing the radical scavenging activity by 78%. Molecular docking research, on the other hand, was carried out for the analyzed candidates (1-7) to study their mechanism of action as EGFR inhibitors. In silico absorption, distribution, metabolism, excretion, and toxicity tests were also performed to explain the physicochemical features of the examined derivatives.