Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors

TOKALI F. S., Demir Y., TÜRKEŞ C., Dincer B., BEYDEMİR Ş.

DRUG DEVELOPMENT RESEARCH, cilt.84, sa.2, ss.275-295, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 84 Sayı: 2
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1002/ddr.22031
  • Dergi Adı: DRUG DEVELOPMENT RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.275-295
  • Anadolu Üniversitesi Adresli: Evet

Özet

Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series of novel acetic acid derivatives containing quinazolin-4(3H)-one ring (1-22) was synthesized and tested for in vitro AR inhibitory effect. All the target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat. Among them, Compound 19, named 2-(4-[(2-[(4-methylpiperazin-1-yl)methyl]-4-oxoquinazolin-3(4H)-ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a K-I value of 61.20 +/- 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF-7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity against the normal L929 cells. The synthesized compounds' (1-22) absorption, distribution, metabolism, and excretion properties were also evaluated. Molecular docking simulations were used to look into the possible binding mechanisms of these inhibitors against AR.