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Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: a novel class of 5-lipoxygenase inhibitors.
Bioorg Med Chem Lett. 2008 Jul 15; 18(14):4195-8.BM

Abstract

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO(2)NH(2) group was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and a N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three regioisomers inhibited 5-lipoxygenase (5-LOX), where the relative potency order was 2-SO(2)NH(2) (IC(50)=10 microM) >3-SO(2)NH(2) (IC(50)=15 microM) >4-SO(2)NH(2) (IC(50)=68 microM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC(50)=35 microM). The 2-SO(2)NH(2) regioisomer (ED(50)=86.0mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED(50)=128.9 mg/kg) and marginally less potent than ibuprofen (ED(50)=67.4 mg/kg). The N-hydroxypyridin-2(1H)one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs.

Authors+Show Affiliations

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18541424

Citation

Chowdhury, Morshed Alam, et al. "Synthesis and Biological Evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene Regioisomers: a Novel Class of 5-lipoxygenase Inhibitors." Bioorganic & Medicinal Chemistry Letters, vol. 18, no. 14, 2008, pp. 4195-8.
Chowdhury MA, Chen H, Abdellatif KR, et al. Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: a novel class of 5-lipoxygenase inhibitors. Bioorg Med Chem Lett. 2008;18(14):4195-8.
Chowdhury, M. A., Chen, H., Abdellatif, K. R., Dong, Y., Petruk, K. C., & Knaus, E. E. (2008). Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: a novel class of 5-lipoxygenase inhibitors. Bioorganic & Medicinal Chemistry Letters, 18(14), 4195-8. https://doi.org/10.1016/j.bmcl.2008.05.071
Chowdhury MA, et al. Synthesis and Biological Evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene Regioisomers: a Novel Class of 5-lipoxygenase Inhibitors. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4195-8. PubMed PMID: 18541424.
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TY - JOUR T1 - Synthesis and biological evaluation of 1-(benzenesulfonamido)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers: a novel class of 5-lipoxygenase inhibitors. AU - Chowdhury,Morshed Alam, AU - Chen,Hua, AU - Abdellatif,Khaled R A, AU - Dong,Ying, AU - Petruk,Kenneth C, AU - Knaus,Edward E, Y1 - 2008/05/22/ PY - 2008/04/04/received PY - 2008/05/16/revised PY - 2008/05/16/accepted PY - 2008/6/11/pubmed PY - 2008/11/18/medline PY - 2008/6/11/entrez SP - 4195 EP - 8 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 18 IS - 14 N2 - A hitherto unknown class of linear acetylene regioisomers were designed such that a SO(2)NH(2) group was located at the ortho-, meta-, or para-position of the acetylene C-1 phenyl ring, and a N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three regioisomers inhibited 5-lipoxygenase (5-LOX), where the relative potency order was 2-SO(2)NH(2) (IC(50)=10 microM) >3-SO(2)NH(2) (IC(50)=15 microM) >4-SO(2)NH(2) (IC(50)=68 microM) relative to the reference drug nordihydroguaiaretic acid (NDGA; IC(50)=35 microM). The 2-SO(2)NH(2) regioisomer (ED(50)=86.0mg/kg po) exhibited excellent oral anti-inflammatory (AI) activity that was more potent than aspirin (ED(50)=128.9 mg/kg) and marginally less potent than ibuprofen (ED(50)=67.4 mg/kg). The N-hydroxypyridin-2(1H)one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/18541424/Synthesis_and_biological_evaluation_of_1__benzenesulfonamido__2_[5__N_hydroxypyridin_2_1H__one_]acetylene_regioisomers:_a_novel_class_of_5_lipoxygenase_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(08)00579-9 DB - PRIME DP - Unbound Medicine ER -