Bioactivity, cytotoxicity, and molecular modeling studies of novel sulfonamides as dual inhibitors of carbonic anhydrases and acetylcholinesterase

被引:20
|
作者
Gulee, Ozcan [1 ]
Turkes, Cuneyt [2 ]
Arslan, Mustafa [1 ]
Demir, Yeliz [2 ,3 ]
Dincer, Busra [4 ]
Ece, Abdulilah [5 ]
Kufrevioglu, Omer Irfan [6 ]
Beydemir, Sukru [7 ]
机构
[1] Sakarya Univ, Dept Chem, Fac Sci, TR-54187 Sakarya, Turkiye
[2] Erzincan Binali Yildirim Univ, Fac Pharm, Dept Biochem, TR-24002 Erzincan, Turkiye
[3] Ardahan Univ, Nihat Delibalta Gole Vocat High Sch, Dept Pharm Serv, TR-75700 Ardahan, Turkiye
[4] Ondokuz Mayis Univ, Fac Pharm, Dept Pharmacol, TR-55200 Samsun, Turkiye
[5] Biruni Univ, Fac Pharm, Dept Pharmaceut Chem, TR-34010 Istanbul, Turkiye
[6] Ataturk Univ, Fac Sci, Dept Chem, TR-25240 Erzurum, Turkiye
[7] Anadolu Univ, Fac Pharm, Dept Biochem, TR-26470 Eskisehir, Turkiye
关键词
Carbonic anhydrase; Sulfonamide; Selective inhibitor; Cytotoxicity; In silico study; ESTERASE-ACTIVITIES; DRUG DISCOVERY; COMPLEXES; DISEASE; AGENTS;
D O I
10.1016/j.molliq.2024.125558
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
In the present medical epoch, the prevailing approach of drug discovery, which focuses on inhibiting a single target, has been superseded by the concept of designing drugs that target more than one specific site. Herein, we present the design and synthesis of a novel series of 1-oxo-3,4-dihydronaphthalene substituted sulfonamides (5aj) with human carbonic anhydrase (hCA) and acetylcholinesterase (AChE) inhibitory activities as potential dualtarget agents. The design of target compounds 5a-j incorporated two key elements: i) The sulfonamide group, which is widely recognized for its high affinity for the active site of hCAs, and ii) the effectiveness of 2-benzylidene-1-tetralone class compounds in some neurodegenerative disorders. All reported sulfonamides were evaluated for their inhibitory effect against hCA I, II isoforms, and AChE. Both hCAs, and AChE were potently inhibited by 5a-j with KI constants in the nanomolar range; 47.71-113.20 nM, 28.05-206.60 nM, and 87.38-136.60 nM, respectively, compared to standard inhibitors, acetazolamide (KIs of 439.17 and 98.28 nM for hCA I and hCA II, respectively) and tacrine (KI of 159.61 nM). 5i exhibited the best multi-target inhibitory activity against hCA I (KI of 47.71 nM), hCA II (KI of 30.75 nM), and AChE (KI of 88.97 nM), while 5b showed a selectivity index (hCA I/II) of 3.61. Moreover, a cytotoxic activity assay for sulfonamides 5a-j was applied on the human breast adenocarcinoma MCF-7 cell line as well as on the non-tumoral mouse fibroblast L929 cell. Thereafter, extensive molecular dynamics simulations revealed the dynamic behavior of ligand/enzyme complex and predicted vital ligand contacts in the binding pocket.
引用
收藏
页数:12
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