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

  • ACS Omega. 2022 Dec 3;7(49):45535-45544. doi: 10.1021/acsomega.2c06219.
Sanaa A Ahmed  1 ,  Moumen S Kamel  2 ,  Moustafa O Aboelez  3 ,  Xiang Ma  4 ,  Ahmed A Al-Karmalawy  5 ,  Sayed A S Mousa  6 ,  Elders Kh Shokr  7 ,  H Abdel-Ghany  2 ,  Amany Belal  8  9 ,  Mohamed A El Hamd  10  11 ,  Zafer S Al Shehri  12 ,  Mahmoud Abd El Aleem Ali Ali El-Remaily  2
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.
PMID: 36530244 DOI: 10.1021/acsomega.2c06219
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 (EGFRWT) and EGFR790M. 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.

Products