Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif


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Güleç Ö., Türkeş C., Arslan M., Demir Y., Yeni Y., Hacımüftüoğlu A., ...Daha Fazla

MOLECULAR DIVERSITY, cilt.26, sa.5, ss.2825-2845, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 26 Sayı: 5
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1007/s11030-022-10422-8
  • Dergi Adı: MOLECULAR DIVERSITY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.2825-2845
  • Anahtar Kelimeler: 1,3,4-oxadiazol, Acetylcholinesterase, Carbonic anhydrase, In silico study, N-substituted sulfonyl amide, CALCIUM-CHANNEL BLOCKERS, CARBONIC-ANHYDRASE I, SULFONAMIDE DERIVATIVES, BIOLOGICAL EVALUATION, MOLECULAR DOCKING, FOLIC-ACID, ACETYLCHOLINESTERASE, VITRO, DESIGN, 4-THIAZOLIDINONE
  • Atatürk Üniversitesi Adresli: Evet

Özet

The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and hCAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and hCAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N-substituted sulfonyl amide derivatives (6a-j) were determined to be highly potent inhibitors for AChE and hCAs (K(I)s are in the range of 23.11-52.49 nM, 18.66-59.62 nM, and 9.33-120.80 nM for AChE, hCA I, and hCA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SYSY cell line, compounds 6a, 6d, and 6h, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and hCAIs. The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs.