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1.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
2.
J Enzyme Inhib Med Chem ; 35(1): 50-58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31656107

RESUMO

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).


Assuntos
Hipoglicemiantes/farmacologia , Oxazinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
3.
J Enzyme Inhib Med Chem ; 35(1): 227-234, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752563

RESUMO

A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 185: 111786, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31671308

RESUMO

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3-d]pyrimidine and thieno[3,2-d] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N-(4-((3,5-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)cinnamamide 8e and (E)-N-(4-((3,4-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC50 values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds.


Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Citotoxinas/farmacologia , Desenho de Drogas , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/síntese química , Cinamatos/química , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
5.
J Enzyme Inhib Med Chem ; 35(1): 311-324, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31809612

RESUMO

Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC50 value of 1.97 µM against M-NFS-60 cells and good GIT absorption with Pe value of 19.0 ± 1.1 × 10-6 cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Proteínas Quinases Associadas com Morte Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Associadas com Morte Celular/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 185: 111808, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683103

RESUMO

Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 µM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 µM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Pirimidinas/farmacologia , Tiadiazóis/farmacologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/química
7.
Eur J Med Chem ; 185: 111866, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734023

RESUMO

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.


Assuntos
Acetamidas/farmacologia , Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Aminas/síntese química , Aminas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , HIV-1/enzimologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
8.
Eur J Med Chem ; 185: 111874, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31735575

RESUMO

The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 µM against WT and 0.0104 µM against the K103N mutant strain, low cytotoxicity (CC50 > 221 µM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


Assuntos
Acetamidas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Acetamidas/síntese química , Acetamidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
9.
AAPS PharmSciTech ; 20(8): 326, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659558

RESUMO

Present study was aimed to increase the oral bioavailability and reduce the fast fed variability of Ibrutinib by developing nanosuspension by simple precipitation-ultrasonication method. A three factor, three level, box-behnken design was used for formulation optimization using pluronic F-127 as stabilizer. Size and polydispersity index of the developed formulations were in the range of 278.6 to 453.2 nm and 0.055 to 0.198, respectively. Field emission scanning electron microscope (FESEM) revealed discrete units of nanoparticles. Further, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies confirmed the transformation of crystal drug to amorphous. The amorphous nature was retained after 6-month storage at room temperature. Size reduction to nano range and polymorphic transformation (crystalline to amorphous) increased the solubility of nanosuspension (21.44-fold higher as compared to plain drug). In vivo studies of plain drug suspension displayed a significant pharmacokinetic variation between fasting and fed conditions. The formulation had shown increased Cmax (3.21- and 3.53-fold), AUC0-t (5.21- and 5.83-fold) in fasting and fed states compared to that of values obtained for plain drug in fasting state (Cmax 48.59 ± 3.30 ng/mL and AUC0-t 137.20 ± 35.47 ng.h/mL). Significant difference was not observed in the pharmacokinetics of nanosuspension in fasting and fed states. The formulation had improved solubility in the intestinal pH, which might be the driving force behind the decreased precipitation and increased absorption at intestinal region. Optimistic results demonstrated nanosuspension as a promising approach for increasing the solubility, extent of absorption and diminishing the fast fed variability.


Assuntos
Desenho de Drogas , Nanopartículas/química , Nanopartículas/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Masculino , Nanopartículas/administração & dosagem , Tamanho da Partícula , Poloxâmero/química , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Ratos , Ratos Wistar , Solubilidade , Suspensões , Difração de Raios X/métodos
10.
Eur J Med Chem ; 183: 111679, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541870

RESUMO

Anti-tubulin polymerization agents can disrupt tumor-vascular to exhibit anti-cancer potency. In this study, a series of substituted (2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone analogues were designed and synthesized as anti-tubulin polymerization agents that interact with colchicine binding site. The anti-proliferative assay indicated that most of the target compounds displayed moderate to high potencies towards five tumor cell lines. The structure-activity relationship of these analogues was summarized. The most potent compound 14 was selected to assay its inhibition on the tubulin polymerization. 14 displayed potent inhibition against tubulin polymerization with an IC50 value of 4.1 ±â€¯0.1 µM. The colchicine competition assay demonstrated that 14 inhibited tubulin polymerization by binding to the colchicine-binding site of tubulin. The molecular modeling study elucidated the binding mode of 14 in the colchicine binding site. The result of confocal immunofluorescent study proved that 14 can quickly disrupt the microtubules of Hela cells in a concentration dependent manner. Some experiments at cellular level were conducted to investigate the effects of 14 on cellular morphology, cell colony formation, cell cycle distribution, cell apoptosis and mitochondrial changes. The results demonstrated that 14 is a potent anti-tubulin agent with strong concentration dependent effect of inhibition of colony formation, induction of G2/M arrest and induction of apoptosis through mitochondrial pathway.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Moduladores de Tubulina/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colchicina/metabolismo , Desenho de Drogas , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia
11.
Eur J Med Chem ; 183: 111716, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550660

RESUMO

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10-8-10-9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 µM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors.


Assuntos
Antineoplásicos/síntese química , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 183: 111690, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31526973

RESUMO

The present paper describes the synthesis and the binding properties for the serotonergic 5-HT7 and 5-HT1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT7R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT7R (Ki = 9.08 and 0.85 nM, respectively) and selectivity over the 5-HT1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT7R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured Ki, further validating the quality of the models.


Assuntos
Pirimidinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
13.
Molecules ; 24(18)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491978

RESUMO

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist.


Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Pirimidinas/química , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 181: 111545, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400706

RESUMO

Abnormal activation of B-cell receptor (BCR) signaling plays a key role in the development of lymphoid malignancies, and could be reverted by the simultaneous inhibition of Lyn, Fyn and Blk, three members of the Src family kinase (SFK). Fyn and Blk are also promising targets for the treatment of some forms of T-cell non-Hodgkin lymphoma which point to the druggability of SFKs for the treatment of these cancers. We recently identified Si308 as a potent Fyn inhibitor, while preliminary data showed that it might also inhibit Lyn and Blk. Here, molecular modelling studies were coupled with enzymatic assays to further investigate the effect of Si308 on Lyn and Blk. A small library of pyrazolo[3,4-d]pyrimidines structurally related to Si308 was synthesized and tested on human lymphoma cell lines. Compound 2h emerged as a new multitarget inhibitor of Lyn, Fyn and Blk endowed with remarkable antiproliferative effects on human B and T lymphoma cell lines. Its favorable ADME properties make the compound suitable for further developments.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Células T/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Quinases da Família src/metabolismo
15.
Eur J Med Chem ; 181: 111558, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369933

RESUMO

In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC50 values ranging from 0.0181 µM to 0.5677 µM. Specifically, compounds 10c and 10e, with IC50 values of 0.0240 µM and 0.0181 µM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
16.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
17.
Eur J Med Chem ; 181: 111559, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376568

RESUMO

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
18.
Arch Pharm (Weinheim) ; 352(9): e1900068, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339194

RESUMO

5-Substituted-6-acetyl-2-amino-7-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte-derived macrophage (THP-1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95-125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow-growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l, showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole-cell mycobacterial drug-efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.


Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/síntese química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacteriaceae/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Células RAW 264.7 , Staphylococcus aureus , Relação Estrutura-Atividade , Células THP-1
19.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340431

RESUMO

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold.


Assuntos
Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 180: 383-397, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325785

RESUMO

Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT1A receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT1A Ki = 8-87 nM; SERT Ki = 8-52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT1A-R and SERT) compared to the precursors.


Assuntos
Pirimidinas/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Receptor 5-HT1A de Serotonina/metabolismo , Triptaminas/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Proteínas de Ligação a RNA/metabolismo , Ratos , Relação Estrutura-Atividade , Triptaminas/química
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