Spiro-fused indoline-quinazoline hybrids as smart bombs against TNF-α-mediated inflammation.

Autor: Elkotamy MS; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt. Electronic address: mahmoud-elkotamy@eru.edu.eg., Elgohary MK; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo 11829, Egypt., Alkabbani MA; Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt., Salem R; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt., Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com., Abdel-Aziz HA; Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: hatem_741@yahoo.com.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Dec; Vol. 283 (Pt 2), pp. 137554. Date of Electronic Publication: 2024 Nov 15.
DOI: 10.1016/j.ijbiomac.2024.137554
Abstrakt: Inflammation is central to numerous diseases, highlighting the need for new anti-inflammatory agents. This study explores the potential of novel spirofused indoline-quinazoline hybrids (4a-p) as anti-inflammatory compounds, inspired by a spiroisatin analogue (VI) that showed modest TNF-α inhibition. We aimed to enhance activity by modifying the isatin scaffold: first, introducing N-alkylation (propyl, butyl, or isobutyl) to improve hydrophobic interactions within the TNF-α dimer active site; second, adding halogens (F, Cl, Br) at the 5-position to increase lipophilicity. Anti-inflammatory activity against TNF-α was confirmed in-vivo for all synthesized analogues, with 4b, 4e, 4k, and 4n emerging as the top candidates. Further studies on these four compounds assessed their analgesic effects, as well as their impact on PGE 2 , NF-κB, paw thickness, and paw weight. In-vitro analyses revealed nanomolar TNFR2-TNF-α binding inhibition for the four leads. Safety evaluations included histopathology, ulcerogenic potential, kidney and liver functions, and acute hemotoxicity. In-silico studies examined drug-likeness, pharmacokinetics, and TNF-α dimer interactions. These results suggest that the four lead compounds possess promising profiles compared to standard therapies.
Competing Interests: Declaration of competing interest There are no interests to declare. The author declared no potential competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: