Pharmacophore-based, rationale design, and efficient synthesis of novel tetrahydrobenzo[b]thiophene candidates as potential dual Topo I/II inhibitors and DNA intercalators.

Autor: Nofal HR; Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt., Al-Karmalawy AA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt., Elmaaty AA; Medicinal Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said, Egypt., Ismail MF; Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt., Ali AK; Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt., Abbass EM; Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Sep; Vol. 357 (9), pp. e2400217. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1002/ardp.202400217
Abstrakt: A series of tetrahydrobenzo[b]thiophene derivatives was designed and synthesized as dual topoisomerase (Topo) I/II inhibitors implicating potential DNA intercalation. Ethyl-2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylate (1) was prepared by modification of the Gewald reaction procedure using a Fe 2 O 3 nanocatalyst and then it was used as a building block for the synthesis of tetrahydrobenzo[b]thiophene candidates (2-14). Interestingly, compound 14 showed the best cytotoxic potential against hepatocellular, colorectal, and breast cancer cell lines (IC 50  = 7.79, 8.10, and 3.53 µM), respectively, surpassing doxorubicin at breast cancer (IC 50  = 4.17 µM). Meanwhile, the Topo I and II inhibition assay displayed that compound 3 could exhibit the best inhibitory potential among the investigated candidates (IC 50  = 25.26 and 10.01 nM), respectively, in comparison to camptothecin (IC 50  = 28.34 nM) and doxorubicin (IC 50  = 11.01 nM), as reference standards. In addition, the DNA intercalation assay showed that compound 14 could display the best binding affinity with an IC 50 value of 77.82 µM in comparison to doxorubicin (IC 50  = 58.03 µM). Furthermore, cell cycle and apoptosis analyses described that compound 3 prompts the G1 phase arrest in michigan cancer foundation-7 cancer cells and increases the apoptosis ratio by 29.31% with respect to untreated cells (2.25%). Additionally, the conducted molecular docking assured the promising binding of the investigated members toward Topo I and II with potential DNA intercalation. Accordingly, the synthesized compounds could be treated as promising anticancer candidates for future optimization.
(© 2024 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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