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1.
PLoS One ; 11(2): e0149131, 2016.
Article in English | MEDLINE | ID: mdl-26863533

ABSTRACT

The most common mutation of CFTR, affecting approximately 90% of CF patients, is a deletion of phenylalanine at position 508 (F508del, ΔF508). Misfolding of ΔF508-CFTR impairs both its trafficking to the plasma membrane and its chloride channel activity. To identify small molecules that can restore channel activity of ΔF508-CFTR, we synthesized and evaluated eighteen novel hydroxypyrazoline analogues as CFTR potentiators. To elucidate potentiation activities of hydroxypyrazolines for ΔF508-CFTR, CFTR activity was measured using a halide-sensitive YFP assay, Ussing chamber assay and patch-clamp technique. Compounds 7p, 7q and 7r exhibited excellent potentiation with EC50 value <10 µM. Among the compounds, 7q (a novel CFTR potentiator, CP7q) showed the highest potentiation activity with EC50 values of 0.88 ± 0.11 and 4.45 ± 0.31 µM for wild-type and ΔF508-CFTR, respectively. In addition, CP7q significantly potentiated chloride conductance of G551D-CFTR, a CFTR gating mutant; its maximal potentiation activity was 1.9 fold higher than the well-known CFTR potentiator genistein. Combination treatment with CP7q and VX-809, a corrector of ΔF508-CFTR, significantly enhanced functional rescue of ΔF508-CFTR compared with VX-809 alone. CP7q did not alter the cytosolic cAMP level and showed no cytotoxicity at the concentration showing maximum efficacy. The hydroxypyrazolines may be potential development candidates for drug therapy of cystic fibrosis.


Subject(s)
Chlorides/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Pyrazoles/therapeutic use , Aminopyridines/therapeutic use , Animals , Bacterial Proteins/chemistry , Benzodioxoles/therapeutic use , Cell Line , Cell Line, Tumor , Cell Membrane/metabolism , Cell Proliferation , Cyclic AMP/metabolism , Epithelial Cells/cytology , Gene Deletion , Genistein/chemistry , Humans , Luminescent Proteins/chemistry , Mutation , Nose/physiology , Patch-Clamp Techniques , Phenylalanine/genetics , Rats , Structure-Activity Relationship , Sulfonamides/therapeutic use
2.
Bioorg Med Chem Lett ; 25(16): 3208-12, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26105196

ABSTRACT

A series of pyrazolylpyrazolines was designed, synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against cytosolic human (h) isozymes hCA I and hCA II as well as transmembrane tumor associated isozymes, hCA IX and hCA XII. All the tested compounds exhibited an excellent CA activity profile against hCA I, hCA II and hCA XII when compared to the reference drug acetazolamide (AZA). Compounds 6d, 6f and 7a-7f have exhibited better inhibition profile against hCA XII (Ki = 0.47-5.1 nM) as compared with AZA (Ki = 5.7 nM) especially, compounds 6a, 7a, 7c and 7d which were nearly 10-fold better than reference drug. Against hCA II, all of the tested compounds were better than the standard drug especially compounds 6c, 6d, 7c and 7d (Ki = 1.1-1.7 nM) were many fold better inhibitors than AZA (Ki = 12.1 nM). In addition, they acted as selective CA inhibitors of isoform hCA XII over the physiological isoform hCA I.


Subject(s)
Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Acetazolamide/pharmacology , Antigens, Neoplasm/drug effects , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase IX , Carbonic Anhydrases/drug effects , Cytosol/enzymology , Humans , Isoenzymes/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Neoplasms/enzymology , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 25(6): 1177-81, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25702850

ABSTRACT

Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25µg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25µg/mL).


Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Carboxylic Acids/chemistry , Animals , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Carboxylic Acids/pharmacology , Carboxylic Acids/therapeutic use , Edema/chemically induced , Edema/drug therapy , Fungi/drug effects , Gram-Positive Bacteria/drug effects , Indomethacin/pharmacology , Indomethacin/therapeutic use , Microbial Sensitivity Tests , Pyrazoles/chemistry , Rats , Thiazoles/chemistry
4.
Bioorg Med Chem ; 22(24): 6945-52, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25456084

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.


Subject(s)
Antigens, Neoplasm/chemistry , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Pyrazoles/chemistry , Antigens, Neoplasm/metabolism , Benzothiazoles/chemistry , Carbonic Anhydrase I/metabolism , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase IX , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Humans , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/metabolism
5.
Eur J Med Chem ; 76: 284-90, 2014 Apr 09.
Article in English | MEDLINE | ID: mdl-24589484

ABSTRACT

A library of 4-functionalized 1,3-diarylpyrazoles (3a-3h, 5a-5g and 6a-6g) was designed, synthesized and evaluated against four human carbonic anhydrase (CA, EC 4.2.1.1) isozymes representing two cytosolic isozymes hCA I and hCA II, and two transmembrane tumor associated ones, hCA IX and hCA XII. All the twenty two tested compounds exhibited excellent CA activity profile against the four CA isozymes when compared to the reference drug acetazolamide. Six of the tested compounds (3a-3b, 3f, 3h, 6a and 6b) displayed low nanomolar affinity (Ki < 5 nM) for hCA IX whereas seven compounds (3a-3b, 3d-3f, 3h and 6f) displayed Ki < 10 nM against hCA XII. In addition, they acted as selective CA inhibitors of isoforms IX and XII over the physiological isoforms I and II.


Subject(s)
Antigens, Neoplasm/drug effects , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/drug effects , Pyrazoles/pharmacology , Sulfonamides/chemistry , Carbonic Anhydrase IX , Carbonic Anhydrase Inhibitors/chemistry , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pyrazoles/chemistry , Benzenesulfonamides
6.
Bioorg Med Chem ; 22(6): 1873-82, 2014 Mar 15.
Article in English | MEDLINE | ID: mdl-24560737

ABSTRACT

Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers 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 isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII.


Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Sulfonamides/pharmacology , Triazoles/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Benzenesulfonamides
7.
Org Med Chem Lett ; 3(1): 9, 2013 Aug 28.
Article in English | MEDLINE | ID: mdl-23981685

ABSTRACT

BACKGROUND: Pyrazole and pyrazolone motifs are well known for their wide range of biological activities such as antimicrobial, anti-inflammatory, and antitumor activities. The incorporation of more than one pharmacophore in a single scaffold is a well known approach for the development of more potent drugs. In the present investigation, a series of differently substituted 4-arylidene pyrazole derivatives bearing pyrazole and pyrazolone pharmacophores in a single scaffold was synthesized. RESULTS: The synthesis of novel 4-arylidene pyrazole compounds is achieved through Knovenagel condensation between 1,3-diaryl-4-formylpyrazoles and 3-methyl-1-phenyl-1H-pyrazol-5-(4H)-ones in good yields. All compounds were evaluated for their in vitro antimicrobial activity. CONCLUSIONS: A series of 4-arylidene pyrazole derivatives was evaluated for their in vitro antimicrobial activity against two Gram-positive (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Pseudomonas fluorescens and Escherichia coli), as well as two pathogenic fungal strains (Candida albicans and Saccharomyces cerevisiae). The majority of the compounds displayed excellent antimicrobial profile against the Gram-positive (B. subtilis and S. aureus), and some of them are even more potent than the reference drug ciprofloxacin.

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