Synthesis and biological validation of novel pyrazole derivatives with anticancer activity guided by 3D-QSAR analysis

Vujasinović, Ines; Paravić-Radičević, Andrea; Mlinarić‐Majerski, Kata; Brajša, Karmen; Bertoša, Branimir

doi:10.1016/j.bmc.2012.01.032

Cited by 68 publications

(29 citation statements)

References 39 publications

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“…Cross validated q 2 of the models were q 2 > 0.3 indicates good internal prediction power of the model. Another parameter for prediction of test set analogues structures is high pred_r 2 > 0.4, which shows good external predictive power of the model 45 .…”

Section: Results: 2d Qsar Model Development and Its Validationmentioning

confidence: 97%

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2017

IJPSR

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Objective: Newly designed antipsoriatic agents which are substituted series of analogues of flavonoids (kaempferol and quercetin) that belong to the subclass flavonols were subjected to (2D-QSAR) analysis using VLIFEMDS-QSARPro software with an intention to derive and understand the possible correlation of biological activity as dependent variable and other descriptors like molecular weight, XLogP values as independent variables. It can be concluded that the current study provides better insight for designing and chemical synthesis of more potent antipsoriatic agents. Methods: Several statistical regression expressions were obtained using variable selection method as simulated annealing coupled with various model building methods like partial least squares (PLS) Regression, multiple linear regression (MLR) etc. Results: For the analogues of both quercetin and kaempferol, a total of 9 QSAR models were generated, each using test set of 15 and training set of 45 similar compounds. The best QSAR model generated by PLS model building method for quercetin was model Q4 with correlation coefficient r 2 of 0.9021 and significant cross validated correlation coefficient q 2 of 0.5791.Similarly, the best QSAR model generated by MLR method, for kaempferol was model K2 with r 2 of 0.687, significant q 2 of 0.5676. Both model Q4 and K2, gave significant results and revealed that presence of SdOE-index, SdsCH count favours the biological activity of quercetin analogues whereas presence of SdssCE-index contributes positively towards biological activity of analogues of kaempferol. This study suggests that such descriptors will be helpful in designing more potent antipsoriatic agents.

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Section: Results: 2d Qsar Model Development and Its Validationmentioning

confidence: 97%

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2017

IJPSR

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“…Quantitative Structure-Activity Relationship (QSAR) studies have been extensively applied to explore the correlations between biological activities and molecular descriptors for different classes of compounds (Soderholm et al, 2006; Vujasinovic et al, 2012). In this study, standard comparative molecular field analysis (CoMFA) was used to explore the relationships between structural features of all tested triterpenoids and their inhibitory effects on hCE1 (Table S1).…”

Section: Resultsmentioning

confidence: 99%

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

et al. 2017

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Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications.

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“…Настоящая работа посвящена исследованию взаимодействия 5-хлорпиразолов 2 и 3 с гидра-зингидратом с целью получения новых произ-водных пиразола как потенциальных биоактив-ных веществ [2][3][4][5][6][7][8][9][10][11][12].…”

Section: взаємодія 1-феніл-5-хлоро-1н-піразол-4-карбоксаміду і 1-феніunclassified

Interaction of 5-chloro-1-phenyl-1H-pyrazole-4-carboxamide and 5-chloro-N-formyl-1-phenyl-1H-pyrazole-4-carboxamide with hydrazine hydrate

Gurenko¹,

Khytova²,

Klyuchko³

et al. 2014

J. org. pharm. chem.

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Synthesis and biological validation of novel pyrazole derivatives with anticancer activity guided by 3D-QSAR analysis

Cited by 68 publications

References 39 publications

Untitled

Untitled

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1

Interaction of 5-chloro-1-phenyl-1H-pyrazole-4-carboxamide and 5-chloro-N-formyl-1-phenyl-1H-pyrazole-4-carboxamide with hydrazine hydrate

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