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4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII.
Bioorg Med Chem. 2014 Dec 15; 22(24):6945-52.BM

Abstract

A series of 24 novel heterocyclic compounds-functionalized at position 4 with aldehyde (5a-5f), carboxylic acid (6a-6f), nitrile (7a-7f) and oxime (8a-8f) functional groups-bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a-6f showed medium-weak inhibitory potential with Ki values in the range of 157-690nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with Ki values of compounds 5a, 5d, 5f, 6a-6f, 8d and 8f lower than 12nM (Ki of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed Ki in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with Ki values of 2.8nM and 5.5nM, respectively.

Authors+Show Affiliations

Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy.Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India. Electronic address: pksharma@kuk.ac.in.

Pub Type(s)

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

Language

eng

PubMed ID

25456084

Citation

SitaRam, , et al. "4-Functionalized 1,3-diarylpyrazoles Bearing 6-aminosulfonylbenzothiazole Moiety as Potent Inhibitors of Carbonic Anhydrase Isoforms hCA I, II, IX and XII." Bioorganic & Medicinal Chemistry, vol. 22, no. 24, 2014, pp. 6945-52.
SitaRam , Ceruso M, Khloya P, et al. 4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII. Bioorg Med Chem. 2014;22(24):6945-52.
SitaRam, ., Ceruso, M., Khloya, P., Supuran, C. T., & Sharma, P. K. (2014). 4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII. Bioorganic & Medicinal Chemistry, 22(24), 6945-52. https://doi.org/10.1016/j.bmc.2014.10.018
SitaRam , et al. 4-Functionalized 1,3-diarylpyrazoles Bearing 6-aminosulfonylbenzothiazole Moiety as Potent Inhibitors of Carbonic Anhydrase Isoforms hCA I, II, IX and XII. Bioorg Med Chem. 2014 Dec 15;22(24):6945-52. PubMed PMID: 25456084.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I, II, IX and XII. AU - SitaRam,, AU - Ceruso,Mariangela, AU - Khloya,Poonam, AU - Supuran,Claudiu T, AU - Sharma,Pawan K, Y1 - 2014/10/22/ PY - 2014/09/01/received PY - 2014/10/10/revised PY - 2014/10/14/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/8/4/medline KW - 6-Aminosulfonylbenzothiazole KW - Acetazolamide KW - Carbonic anhydrase isoforms I, II, IX, XII KW - Pyrazoles SP - 6945 EP - 52 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 22 IS - 24 N2 - A series of 24 novel heterocyclic compounds-functionalized at position 4 with aldehyde (5a-5f), carboxylic acid (6a-6f), nitrile (7a-7f) and oxime (8a-8f) functional groups-bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a-6f showed medium-weak inhibitory potential with Ki values in the range of 157-690nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with Ki values of compounds 5a, 5d, 5f, 6a-6f, 8d and 8f lower than 12nM (Ki of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed Ki in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with Ki values of 2.8nM and 5.5nM, respectively. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25456084/4_Functionalized_13_diarylpyrazoles_bearing_6_aminosulfonylbenzothiazole_moiety_as_potent_inhibitors_of_carbonic_anhydrase_isoforms_hCA_I_II_IX_and_XII_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(14)00739-1 DB - PRIME DP - Unbound Medicine ER -