Design, synthesis, and molecular docking of novel 3,5-disubstituted-1,3,4-oxadiazole derivatives as iNOS inhibitors

被引:8
作者
Koksal, Meric [1 ]
Dedeoglu-Erdogan, Ayca [1 ]
Bader, Marwa [1 ,2 ]
Gurdal, Enise E. [1 ,3 ]
Sippl, Wolfgang [3 ]
Reis, Rengin [4 ,5 ]
Ozgurbuz, Melda [6 ]
Sipahi, Hande [4 ]
Celik, Turgay [6 ]
机构
[1] Yeditepe Univ, Dept Pharmaceut Chem, Fac Pharm, TR-34755 Istanbul, Turkey
[2] Omar Al Mukhtar Univ, Dept Pharmaceut Chem, Fac Pharm, Al Bayda, Libya
[3] Martin Luther Univ Halle Wittenberg, Dept Pharmaceut Chem & Clin Pharm, Halle, Saale, Germany
[4] Yeditepe Univ, Dept Pharmaceut Toxicol, Fac Pharm, Istanbul, Turkey
[5] Acibadem Univ, Dept Pharmaceut Toxicol, Fac Pharm, Istanbul, Turkey
[6] Yeditepe Univ, Dept Pharmacol, Fac Pharm, Istanbul, Turkey
关键词
1,3,4-oxadiazole; anti-inflammatory; docking study; nitric oxide; PGE(2); NITRIC-OXIDE; BIOLOGICAL EVALUATION; PGE(2);
D O I
10.1002/ardp.202000469
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
To obtain new anti-inflammatory agents, recent studies have aimed to replace the carboxylate functionality of nonsteroidal anti-inflammatory drugs with less acidic heterocyclic bioisosteres like 1,3,4-oxadiazole to protect the gastric mucosa from free carboxylate moieties. In view of these observations, we designed and synthesized a series of 3,5-disubstituted-1,3,4-oxadiazole derivatives as inhibitors of prostaglandin E-2 (PGE(2)) and NO production with an improved activity profile. As initial screening, and to examine the anti-inflammatory activities of the compounds, the inhibitions of the productions of lipopolysaccharide-induced NO and PGE(2) in RAW 264.7 macrophages were evaluated. The biological assays showed that, compared with indomethacin, compounds 5a, 5g, and 5h significantly inhibited NO production with 12.61 +/- 1.16, 12.61 +/- 1.16, and 18.95 +/- 3.57 mu M, respectively. Consequently, the three compounds were evaluated for their in vivo anti-inflammatory activities. Compounds 5a, 5g, and 5h showed a potent anti-inflammatory activity profile almost equivalent to indomethacin at the same dose in the carrageenan-induced paw edema test. Moreover, the treatment with 40 mg/kg of 5h produced significant anti-inflammatory activity data. Furthermore, docking studies were performed to reveal possible interactions with the inducible nitric oxide synthase enzyme. Docking results were able to rationalize the biological activity data of the studied inhibitors. In summary, our data suggest that compound 5h is identified as a promising candidate for further anti-inflammatory drug development with an extended safety profile.
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页数:9
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共 35 条
[1]   Novel pyrazolopyrimidine derivatives targeting COXs and iNOS enzymes; design, synthesis and biological evaluation as potential anti-inflammatory agents [J].
Abdelazeem, Ahmed H. ;
Abdelatef, Shaimaa A. ;
El-Saadi, Mohammed T. ;
Omar, Hany A. ;
Khan, Shabana I. ;
McCurdy, Christopher R. ;
El-Moghazy, Samir M. .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2014, 62 :197-211
[2]   Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents [J].
Aboraia, AS ;
Abdel-Rahman, HM ;
Mahfouz, NM ;
El-Gendy, MA .
BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (04) :1236-1246
[3]   Nitric oxide synthases: structure, function and inhibition [J].
Alderton, WK ;
Cooper, CE ;
Knowles, RG .
BIOCHEMICAL JOURNAL, 2001, 357 (03) :593-615
[4]   Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE2 in LPS-induced RAW 264.7 cells [J].
An, Ji-Young ;
Lee, Hwi-Ho ;
Shin, Ji-Sun ;
Yoo, Hyung-Seok ;
Park, Jong Seon ;
Son, Seung Hwan ;
Kim, Sang Won ;
Yu, Jihyun ;
Lee, Jun ;
Lee, Kyung-Tae ;
Kim, Nam-Jung .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (11) :2613-2616
[5]   Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents [J].
Bekhit, AA ;
Abdel-Aziem, T .
BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (08) :1935-1945
[6]   Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives [J].
Bhandari, Shashikant V. ;
Bothara, Kailash G. ;
Raut, Mayuresh K. ;
Patil, Ajit A. ;
Sarkate, Aniket P. ;
Mokale, Vinod J. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2008, 16 (04) :1822-1831
[7]   Piperazine and piperidine-substituted 7-hydroxy coumarins for the development of anti-inflammatory agents [J].
Buran, Kerem ;
Reis, Rengin ;
Sipahi, Hande ;
Bayram, F. Esra Onen .
ARCHIV DER PHARMAZIE, 2021, 354 (07)
[8]   Facile conversion of racemic ibuprofen to (S)-ibuprofen [J].
Chavez-Flores, David ;
Salvador, James M. .
TETRAHEDRON-ASYMMETRY, 2012, 23 (3-4) :237-239
[9]   The dual personality of NO [J].
Colasanti, M ;
Suzuki, H .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2000, 21 (07) :249-252
[10]   Cyclooxygenase inhibitors - current status and future prospects [J].
Dannhardt, G ;
Kiefer, W .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2001, 36 (02) :109-126