Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

Giampietro, Letizia; Ammazzalorso, Alessandra; Giancristofaro, Antonella; Lannutti, F; Bettoni, Giancarlo; Filippis, Barbara De; Fantacuzzi, Marialuigia; Maccallini, Cristina; Petruzzelli, Michele; Morgano, Annalisa; Moschetta, Antonio; Amoroso, Rosa

doi:10.1021/jm900878u

Cited by 25 publications

(14 citation statements)

References 44 publications

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“…In 2009, several 2-benzothiazolylthioalkanoic acids 39 (Figure 18) were synthesized and evaluated for their human PPARγ transactivation activity [109]. Overall, the potencies of some newly designed agonists were slightly higher than those of typical fibrates, such as clofibrate.…”

Section: Biologically Active 2-mercaptobenzothiazolesmentioning

confidence: 99%

“…Another group of researchers synthesized a series of 2-benzothiazolylthioalkanoic acids 52 (Figure 29) through systematic structural modifications of clofibric acid and evaluated them for human PPARα transactivation activity, with the aim of obtaining new hypolipidemic compounds [125]. Overall, the potencies of some newly designed agonists were slightly higher than those of typical fibrates, such as clofibrate.…”

Section: Biologically Active 2-mercaptobenzothiazolesmentioning

confidence: 99%

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Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

Azam¹

2012

Sci. Pharm.

101

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2-Mercaptobenzothiazoles are an important class of bioactive and industrially important organic compounds. These compounds are reported for their antimicrobial and antifungal activities, and are subsequently highlighted as a potent mechanism-based inhibitor of several enzymes like acyl coenzyme A cholesterol acyltransferase, monoamine oxidase, heat shock protein 90, cathepsin D, and c-Jun N-terminal kinases. These derivatives are also known to possess antitubercular, anti-inflammatory, antitumor, amoebic, antiparkinsonian, anthelmintic, antihypertensive, antihyperlipidemic, antiulcer, chemoprotective, and selective CCR3 receptor antagonist activity. This present review article focuses on the pharmacological profile of 2-mercaptobenzothiazoles with their potential activities.

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Section: Biologically Active 2-mercaptobenzothiazolesmentioning

confidence: 99%

Section: Biologically Active 2-mercaptobenzothiazolesmentioning

confidence: 99%

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

Azam¹

2012

Sci. Pharm.

101

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“…These compounds, considered as clofibric acid analogues, were basically PPAR agonists with the S isomers more potent than the R counterparts. In the series of optically active ligands, the best findings were obtained with the isomer (108) [127]. …”

Section: -Substituted Aryloxyacetic Acid Derivatives (Fibrates)mentioning

confidence: 99%

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

Loiodice

Pochetti²

2011

CTMC

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Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in which chirality is a crucial point in determining the PPAR binding mode are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.

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“…In previous papers from the Italian co‐authors’ laboratories1,2 synthesis and in vitro bioactivity data have been reported for a representative series of structurally diverse derivatives of clofibric acid, in particular heteroarylalkanoic analogues (Scheme 1, Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…Especially interesting from the point of view of a search for potential drugs, guided by quantitative structure‐activity relationships (QSAR), appeared to be the EC 50 values, determined for 18 agents in the human peroxisome proliferator‐activated receptor α (PPARα) transactivation test 2. These EC 50 data (in µM) spanned three orders of magnitude and were evenly distributed (Table 1S in Supporting Information).…”

Section: Introductionmentioning

confidence: 99%

QSAR, QSPR and QSRR in Terms of 3‐D‐MoRSE Descriptors for In Silico Screening of Clofibric Acid Analogues

Tullio

Maccallini

Ammazzalorso

et al. 2012

Molecular Informatics

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A series of 27 analogues of clofibric acid, mostly heteroarylalkanoic derivatives, have been analyzed by a novel high-throughput reversed-phase HPLC method employing combined gradient of eluent's pH and organic modifier content. The such determined hydrophobicity (lipophilicity) parameters, log kw , and acidity constants, pKa , were subjected to multiple regression analysis to get a QSRR (Quantitative StructureRetention Relationships) and a QSPR (Quantitative Structure-Property Relationships) equation, respectively, describing these pharmacokinetics-determining physicochemical parameters in terms of the calculation chemistry derived structural descriptors. The previously determined in vitro log EC50 values - transactivation activity towards PPARα (human Peroxisome Proliferator-Activated Receptor α) - have also been described in a QSAR (Quantitative StructureActivity Relationships) equation in terms of the 3-D-MoRSE descriptors (3D-Molecule Representation of Structures based on Electron diffraction descriptors). The QSAR model derived can serve for an a priori prediction of bioactivity in vitro of any designed analogue, whereas the QSRR and the QSPR models can be used to evaluate lipophilicity and acidity, respectively, of the compounds, and hence to rational guide selection of structures of proper pharmacokinetics.

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Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

Cited by 25 publications

References 44 publications

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

QSAR, QSPR and QSRR in Terms of 3‐D‐MoRSE Descriptors for In Silico Screening of Clofibric Acid Analogues

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