Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, and in silico studies.

Autor: Al-Muntaser SM; Department of Chemistry, Faculty of Science, Ain Shams University Abbassiya 11566 Cairo Egypt eslammorad@sci.asu.edu.eg., Al-Karmalawy AA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University 6th of October City Giza 12566 Egypt akarmalawy@acu.edu.eg., El-Naggar AM; Department of Chemistry, Faculty of Science, Ain Shams University Abbassiya 11566 Cairo Egypt eslammorad@sci.asu.edu.eg., Ali AK; Department of Chemistry, Faculty of Science, Ain Shams University Abbassiya 11566 Cairo Egypt eslammorad@sci.asu.edu.eg., Abd El-Sattar NEA; Department of Chemistry, Faculty of Science, Ain Shams University Abbassiya 11566 Cairo Egypt eslammorad@sci.asu.edu.eg., Abbass EM; Department of Chemistry, Faculty of Science, Ain Shams University Abbassiya 11566 Cairo Egypt eslammorad@sci.asu.edu.eg.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2023 Apr 18; Vol. 13 (18), pp. 12184-12203. Date of Electronic Publication: 2023 Apr 18 (Print Publication: 2023).
DOI: 10.1039/d3ra00416c
Abstrakt: In this article, we continued our previous effort to develop new selective anticancer candidates based on the basic pharmacophoric requirements of both EGFR and VEGFR-2 inhibitors. Therefore, twenty-two novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives were designed and examined as dual EGFR/VEGFR-2 inhibitors. Besides, the previously reported antimicrobial activities of the aforementioned nuclei motivated us to screen their antibacterial and antifungal activities as well. First, the antitumor activities of the newly synthesized derivatives were evaluated against two cancer cell lines (HepG-2 and MCF-7). Notably, compounds 2a, 6a, 7a, 10b, 15a, and 18a exhibited superior anticancer activities against both HepG-2 and MCF-7 cancer cell lines. These candidates were selected to further evaluate their anti-EGFR and anti-VEGFR-2 potentialities which were found to be very promising compared to erlotinib and sorafenib, respectively. Both 10b and 2a derivatives achieved better dual EGFR/VEGFR-2 inhibition with IC 50 values of 0.161 and 0.141 μM and 0.209 and 0.195 μM, respectively. Moreover, the most active 10b was selected to evaluate the exact phase of cell cycle arrest and to investigate the exact mechanism of cancer cell death whether it be due to apoptosis or necrosis. On the other hand, all the synthesized compounds were tested against Gram-positive bacteria such as S. aureus and B. subtilis as well as Gram-negative bacteria such as E. coli and P. aeuroginosa . Also, the antifungal activity was investigated against C. albicans and A. flavus strains. The findings of the antimicrobial tests revealed that most of the investigated compounds exhibited strong to moderate antibacterial and antifungal effects. Furthermore, to understand the pattern by which the investigated compounds bound to the active site, all the newly synthesized candidates were subjected to two different docking processes into the EGFR and VEGFR-2 binding sites. Besides, we tried to correlate compound 10b and the reference drugs (erlotinib and sorafenib) through DFT calculations. Finally, following the biological data of the new pyrazole, pyridine, and pyrimidine derivatives as anticancer and antimicrobial candidates, we concluded a very interesting SAR for further optimization.
Competing Interests: The authors declared no conflict of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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