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1.
ACS Omega ; 4(21): 19420-19436, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31763566

RESUMO

An efficient Ni(ClO4)2·6H2O-promoted amidoalkylation reaction for the synthesis of 3-substituted isoindolinones involving various γ-hydroxy lactams and nucleophiles has been successfully developed. The transformation proceeds with both carbon (ketones and arenes) and heteroatom (alcohols, thiols, and amines) nucleophiles and in both intermolecular and intramolecular manners. The prominent features of the present strategy are wide substrate scope, excellent group tolerability, and moderate to good yields (up to 96% yield). The present strategy is also characterized by remarkable superiority over the current synthetic methods. Furthermore, the reaction could be scaled up to the multigram scale.

2.
Angew Chem Int Ed Engl ; 58(14): 4547-4551, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30790405

RESUMO

The overproduction of HOCl is highly correlated with diseases such as atherosclerosis, rheumatoid arthritis, and cancer. Whilst acting as a marker of these diseases, HOCl might also be used as an activator of prodrugs or drug delivery systems for the treatment of the corresponding disease. In this work, a new platform of HOCl probes has been developed that integrates detection, imaging, and therapeutic functions. The probes can detect HOCl, using both NIR emission and the naked eye in vitro, with high sensitivity and selectivity at ultralow concentrations (the detection limit is at the nanomolar level). Basal levels of HOCl can be imaged in HL-60 cells without special stimulation. Moreover, the probes provided by this platform can rapidly release either amino- or carboxy-containing compounds from prodrugs, during HOCl detection and imaging, to realize a therapeutic effect.

3.
Bioorg Med Chem Lett ; 29(3): 383-388, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579795

RESUMO

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 µM for 1g against human URAT1 vs 7.20 µM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.


Assuntos
Ácidos Carboxílicos/farmacologia , Ésteres/farmacologia , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Triazóis/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Gota/metabolismo , Humanos , Hiperuricemia/metabolismo , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Triazóis/química
4.
Molecules ; 23(2)2018 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-29382075

RESUMO

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 µM against human URAT1 for 1h vs. 7.18 µM and 0.28 µM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.


Assuntos
Metano/análogos & derivados , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/metabolismo , Uricosúricos/síntese química , Benzobromarona/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Radioisótopos de Carbono , Desenho de Fármacos , Expressão Gênica , Células HEK293 , Humanos , Metano/síntese química , Metano/farmacologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Tioglicolatos/farmacologia , Triazóis/farmacologia , Uricosúricos/farmacologia
5.
Med Chem ; 13(3): 260-281, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27633583

RESUMO

BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. METHODS: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. RESULTS: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 µM and 0.094 µM, respectively, against human URAT1 vs 7.18 µM for lesinurad). CONCLUSION: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.


Assuntos
Descoberta de Drogas , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Compostos de Sulfidrila/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Triazóis/química
6.
Molecules ; 21(11)2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27854343

RESUMO

In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 µM against human URAT1 for 1q vs 7.18 µM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.


Assuntos
Ácido Butírico/química , Ácido Butírico/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Butírico/síntese química , Linhagem Celular , Técnicas de Química Combinatória , Humanos , Concentração Inibidora 50 , Estrutura Molecular
7.
Med Chem ; 11(4): 317-28, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25557661

RESUMO

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas/história , Hipoglicemiantes/síntese química , Hipoglicemiantes/história , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/história , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Desenho de Fármacos , Glucosídeos/síntese química , Glucosídeos/história , Glucosídeos/uso terapêutico , Glicosídeos , História do Século XX , História do Século XXI , Humanos , Hipoglicemiantes/uso terapêutico , Monossacarídeos/síntese química , Monossacarídeos/história , Monossacarídeos/uso terapêutico , Florizina/análogos & derivados , Florizina/síntese química , Florizina/história , Florizina/uso terapêutico , Transportador 2 de Glucose-Sódio/química , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
8.
Med Chem ; 10(3): 304-17, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24059684

RESUMO

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.


Assuntos
Compostos Benzidrílicos/farmacologia , Desoxiglucose/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/química , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/química , Desoxiglucose/farmacologia , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Ratos , Transportador 2 de Glucose-Sódio , Relação Estrutura-Atividade
9.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 3): o405, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476586

RESUMO

The asymmetric unit of the title compound, C17H14BrCl3O, contains two independent mol-ecules with different dihedral angles between the benzene rings [79.2 (1) and 72.7 (1)°]. In the crystal, weak C-H⋯π inter-actions link mol-ecules related by translation along the b axis into two crystallographically independent chains.

10.
Expert Opin Drug Discov ; 7(6): 489-501, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22607210

RESUMO

INTRODUCTION: The copper(I)-catalyzed 1,3-dipolar cycloaddition of alkynes and azides to form 1,2,3-triazoles is the most popular reaction in click chemistry. This reaction is also near-perfect, in terms of its robustness, due to the high degree of reliability and complete specificity. Furthermore, this reaction has been used increasingly in drug discovery, because the formed 1,2,3-triazole can act as both a bioisostere and a linker. AREAS COVERED: This review provides an overview of a most important click reaction, 1,3-dipolar cycloadditions of alkynes and azides, in the drug discovery. EXPERT OPINION: Click chemistry is a very powerful tool, in the drug discovery, because it is very efficient in the creation of compound libraries through combinatorial methodology. However, the 1,2,3-triazole ring itself is not a commonly used pharmacophore and has rarely been found in marketed drugs, demonstrating that there are still some limitations during the use of 1,2,3-triazole in the molecules of drug candidates. Hopefully, in the next decade, we will witness the emergence of 1,2,3-triazole-bearing drugs on the market as this click reaction is used more and more widely in the drug discovery.


Assuntos
Química Farmacêutica/métodos , Química Click/métodos , Técnicas de Química Combinatória/métodos , Descoberta de Drogas/métodos , Alquinos/química , Azidas/química
11.
Eur J Med Chem ; 46(12): 5868-77, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22000925

RESUMO

A series of novel 3-(1H-indole-3-yl)-1H-pyrazole-5-carbohydrazide derivatives 4Ia-n, 4IIa-b and 6 were prepared by hydrazinolysis of ethyl 3-(1H-indole-3-yl)-1H-pyrazole-5-carboxylate with hydrazine hydrate in excellent yields. These new compounds were fully characterized by spectroscopic methods, and the important intermediates 3Ie, 3IIc and 3IId were further confirmed by X-ray crystallography. All the new compounds were evaluated for their cytotoxic activity against 4 human cancer cell lines by MTT method. Some of them exhibited more potent antiproliferative activity against HepG-2, BGC823 and BT474 cell lines than the positive drug 5-fluorourcail. Flow cytometry analysis showed that 4Ik and 4Il arrested the cell cycle at S phase.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrazinas/química , Hidrazinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Antineoplásicos/síntese química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Hidrazinas/síntese química , Modelos Moleculares , Neoplasias/tratamento farmacológico , Pirazóis/síntese química , Relação Estrutura-Atividade
12.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 2): o322, 2010 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-21579752

RESUMO

In the title mol-ecule, C(10)H(12)N(4)O, the tetra-zole and benzene rings form a dihedral angle of 67.52 (2)°. In the crystal, inter-molecular N-H⋯N hydrogen bonds link the mol-ecules into chains along the a axis. The relatively short distance of 3.760 (3) Šbetween the centroids of the tetra-zole rings suggests the existence of π-π inter-actions.

13.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 3): o518, 2010 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21580292

RESUMO

In the title compound, C(13)H(13)Cl(2)N(3)OS, the thia-zole and benzene rings are roughly parallel to one another in two layers [dihedral angle = 5.08 (2)°] because the N-C-C-N-C chain that links the two rings is folded [N-C-C-N torsion angle = 12.0 (2)°] rather than fully extended. An intra-molecular N-H⋯N inter-action occurs. In the crystal, weak inter-molecular N-H⋯N and C-H⋯O inter-actions are present and π-π inter-actions are indicated by the short distances [3.507 (3)-3.665 (2) Å] between the centroids of the thia-zole and benzene rings.

14.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 3): o536, 2010 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-21580307

RESUMO

In the title compound, C(10)H(9)NO(2), the isoxazole and phenyl rings form a dihedral angle of 25.82 (3)°. In the crystal, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into ribbons propagating along [001]. The crystal packing is further stabilized by weak C-H⋯O and C-H⋯N inter-actions.

15.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 8): o2037, 2010 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-21588346

RESUMO

The title compound, C(12)H(16)O(2), is approximately planar (r.m.s. deviation = 0.030 Å), apart from two methyl groups of the tert-butyl unit [deviations of the C atoms = 1.140 (2) and -1.367 (1) Å]. In the crystal, inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into hexa-meric rings with R(6) (6)(48) graph-set motifs.

16.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 8): o2038, 2010 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-21588347

RESUMO

In the title compound, C(16)H(15)BrO(2), the dihedral angle between the benzene rings is 68.5 (2)°. In the crystal structure, mol-ecules are linked by weak C-H⋯O hydrogen bonds into chains parallel to the b axis.

17.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 10): o2372, 2009 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21577837

RESUMO

In the title mol-ecule, C(18)H(18)N(2)O(2), the bicyclic ring system and the benzene ring form a dihedral angle of 13.45 (3)°. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds link mol-ecules into chains propagated along [201].

18.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 12): o3071, 2009 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-21578801

RESUMO

In the title mol-ecule, C(15)H(12)BrClO(2), the two benzene rings form a dihedral angle of 69.30 (3)°. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds link mol-ecules into chains propagating along the b axis.

19.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 2): o372, 2009 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-21581970

RESUMO

The asymmetric unit of the title compound, C(14)H(15)N(3)O(7), contains two independent mol-ecules which are linked into a pseudocentrosymmetric dimer by a π-π inter-action, as shown by the short distance of 3.722 (5) Šbetween the centroids of the benzene rings. An extensive network of weak inter-molecular C-H⋯O hydrogen bonds helps to stabilize the crystal packing.

20.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 4): o923, 2009 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-21582625

RESUMO

The title compound, C(15)H(15)N(3)O(2)S·H(2)O, has been obtained in a search for new imidazo[1,2-b]pyrazole derivatives with better biological activity. The 1H-imidazo[1,2-b]pyrazole plane forms a dihedral angle of 16.90 (3)° with the benzene ring. π-π inter-actions are indicated by the short distance of 3.643 (2) Šbetween the centroids of the benzene and imidazole rings. The crystal structure also involves inter-molecular O-H⋯N hydrogen bonds.

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