Design and evaluation of sulfadiazine derivatives as potent dual inhibitors of EGFR WT and EGFR T790M : integrating biological, molecular docking, and ADMET analysis.

Autor: Abd El-Lateef HM; Department of Chemistry, College of Science, King Faisal University Al-Ahsa 31982 Saudi Arabia hmahmed@kfu.edu.sa.; Department of Chemistry, Faculty of Science Sohag 82524 Egypt., Ezelarab HAA; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University 61519-Minia Egypt hend_aly@minia.edu.eg., Ali AM; Department of Chemistry, Faculty of Science Sohag 82524 Egypt., Alsaggaf AT; Department of Chemistry, Taibah University Madinah Saudi Arabia., Mahdi WA; Department of Pharmaceutics, College of Pharmacy, King Saud University Riyadh 11451 Saudi Arabia., Alshehri S; Department of Pharmaceutics, College of Pharmacy, King Saud University Riyadh 11451 Saudi Arabia., El Hamd MA; Department of Pharmaceutical Chemistry, College of Pharmacy, Shaqra University Shaqra 11961 Saudi Arabia aboelhamdmohamed@su.edu.sa.; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University Qena 83523 Egypt., Aboelez MO; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University Sohag Egypt drmoustafaaboelez@yahoo.com.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2024 Sep 06; Vol. 14 (39), pp. 28608-28625. Date of Electronic Publication: 2024 Sep 06 (Print Publication: 2024).
DOI: 10.1039/d4ra04165h
Abstrakt: A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC 50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFR WT and EGFR T790M protein kinases, with IC 50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC 50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFR WT and EGFR T790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFR WT and EGFR T790M , with binding scores of -6.40 kcal mol -1 and -7.53 kcal mol -1 , respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol -1 , respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFR WT and EGFR T790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.
Competing Interests: The authors declare no conflict of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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