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1.
Eur J Med Chem ; 213: 113173, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33493830

RESUMO

Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI-H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI-H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI-H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI-H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
2.
Biomed Pharmacother ; 134: 111132, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33360050

RESUMO

DNA gyrase and Topoisomerase IV are promising antibacterial drug targets as they regulate bacterial DNA replication and topology. In a quest for novel DNA topoisomerase inhibitors, a multidisciplinary approach was adopted that involves computational prediction of binding sites and molecular modelling followed by green synthesis and biological evaluation of antibacterial activity of spirobenzimidazo quinazolines derivatives. Using basic quantum chemistry principles, we evaluated spirobenzimidazo quinazolines derivatives with their pharmacokinetic profiles. Based on the results of the aforesaid in-silico studies, we synthesized a series of titled compounds using green synthetic methodology that were validated as potential antimicrobial agents. Quantum chemoinformatics based predicted activity for the synthesized compounds 9b, 9c, and 9j was concomitant with biological evaluation of broadspectrum antibacterial activity. Biological evaluation revealed that inhibition of biofilm formation was due to their potential antibacterial activity. We believe that the novel spirobenzimidazo quinazolines have the potential to be alternatives to aminocoumarins and classical quinazolines upon detailed target specific biological studies.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Benzimidazóis/farmacologia , Desenho Assistido por Computador , DNA Girase/metabolismo , Desenho de Fármacos , Quinazolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Bactérias/crescimento & desenvolvimento , Benzimidazóis/síntese química , Sítios de Ligação , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , DNA Girase/química , Química Verde , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Quinazolinas/síntese química , Inibidores da Topoisomerase II/síntese química
3.
J Med Chem ; 63(24): 15906-15945, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33314925

RESUMO

HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC50: 5.4-12 nM) compared to lapatinib (IC50: 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI50: 1.43-2.09 µM) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (∼20-fold) against HER2+ (AU565, BT474) compared to HER2(-) cells. At 0.1 IC50, 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Lapatinib/química , Terapia de Alvo Molecular , Quinazolinas/síntese química , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Receptor ErbB-2/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem Lett ; 30(20): 127472, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781216

RESUMO

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC50 = 0.157 µM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.


Assuntos
Compostos de Anilina/farmacologia , Antivirais/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinazolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/toxicidade , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular , Chlorocebus aethiops , Cricetulus , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/toxicidade , Ratos , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 192: 112185, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32145644

RESUMO

Over the past decade, we described a novel tumour targeted approach that sought to design "combi-molecules" to hit two distinct targets in tumour cells. Here, to generate small combi-molecules with strong DNA damaging potential while retaining EGFR inhibitory potency, we developed the first synthetic strategy to access the 6-N, N-disubstituted quinazoline scaffold and designed JS61 to possess a nitrogen mustard function directly attached to the 6-position of the quinazoline ring. We compared its biological activity with that of structures containing either a hemi mustard or a non-alkylating substituent. Surprisingly, the results showed that JS61, while capable of inducing strong DNA damage, exhibited moderate EGFR inhibitory potency. In contrast, "combi-molecules" with no bulky substituent at the N-6 position (e.g. ZR2002 and JS84) showed stronger EGFR and growth inhibitory potency than JS61 in a panel of lung cancer cells. To rationalize these results, X-ray crystallography and molecular modeling studies were undertaken, and the data obtained indicated that bulkiness of the 6-N,N-disubstituted moieties hinder its binding to the ATP site and affects binding reversibility.


Assuntos
Antineoplásicos/farmacologia , DNA/efeitos dos fármacos , Quinazolinas/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Bovinos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
J Med Chem ; 63(9): 4468-4483, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32023060

RESUMO

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Quinazolinas/uso terapêutico , Quinolonas/uso terapêutico , Regulação Alostérica , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Camundongos Nus , Conformação Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Molecules ; 25(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093392

RESUMO

A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC50 values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC50 values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC50 values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed.


Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Proteínas de Choque Térmico HSP90 , Proteínas de Neoplasias , Neoplasias Experimentais , Quinazolinas , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácido Ascórbico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células MCF-7 , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Enzyme Inhib Med Chem ; 35(1): 598-609, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32009479

RESUMO

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2-13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2-13 with inhibition constants (KIs) ranging from 57.8-740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2-13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 35(1): 511-523, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31939312

RESUMO

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Aldeído Redutase/metabolismo , Animais , Anti-Helmínticos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinazolinas/síntese química , Schistosoma mansoni/enzimologia , Relação Estrutura-Atividade
10.
Mol Divers ; 24(1): 131-139, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30868331

RESUMO

An efficient and simple protocol for the synthesis of trifluoromethylated quinazolines has been described by I2-/KI-promoted oxidative C(sp3)-C(sp2) bond under the optimal oxidative cyclization reaction conditions. The required 2,2,2-trifluoro-N-benzyl-N'-arylacetimidamides are readily prepared from the corresponding acetimidoyl chlorides and benzylamines under a nucleophilic substitution reaction in the form of in situ. The merits of this protocol are the use of inexpensive molecular iodine, metal-free oxidative coupling and good to excellent yields.


Assuntos
Compostos de Iodo/química , Iodo/química , Iodeto de Potássio/química , Quinazolinas/síntese química , Catálise , Ciclização , Modelos Moleculares , Estrutura Molecular
11.
Eur J Med Chem ; 186: 111851, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761381

RESUMO

Forty-eight analogues of CP-31398, an antitumor agent modulated the mutant p53 gene were synthesized and their cytotoxicities against four cancer cell lines with different p-53 status including bladder cell T24 (w-p53), gastric cell MGC-803 (m-p53), prostate cell DU145 (m-p53), prostate cell PC-3 (null-p53), lung cell A549 (w-p53) and normal liver cell line HL-7702 (w-p53) were examined. (E)-2-(4-Nitrostyryl)-4-(3-dimethylaminopropyl)-aminoquinazoline (10ah) was identified as the most potent compound in anti-proliferation against MGC-803 cells, with IC50 lowed to 1.73 µM, far potency than that of CP-31398. Molecular mechanism study revealed that 10ah and CP-31398 differ greatly in mechanism to exert their antitumor properties. 10ah could intercalate into DNA and resulted in significant DNA double-strand break. 10ah-treatment in MGC-803 cells increased the expression of p53, phosphorylated p53 (p-p53), CDK4, p21 to cause cell cycle arrest at G2/M phase, significantly up-regulated the levels of pro-apoptosis proteins Bak, Bax, Bim while down-regulated the anti-apoptosis proteins Bcl-2, Bcl-xL and the levels of cyclin B1, fluctuated the intracellular reactive oxygen species (ROS), Ca2+ and mitochondrial membrane potential, activated Caspase-9 and Caspase-3 to induce apoptosis. 10ah also displayed potent anticancer efficiency against MGC-803 xenograft tumors models, with tumor growth inhibition (TGI) up to 61.8% at 20 mg/kg without obvious toxicity.


Assuntos
Antineoplásicos/farmacologia , Quinazolinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Clivagem do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética
12.
Mini Rev Med Chem ; 20(5): 418-429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31161988

RESUMO

BACKGROUND & OBJECTIVE: Quinazolines and their fused systems are noteworthy in pharmaceutical chemistry due to their wide range of biological activities. METHODS: A direct and efficient approach for the synthesis of new series of fused quinazolines with triazole, thiazole, benzimidazole and tetrazole has been preceded via the reaction of quinazoline thione derivative with halogenated compounds or cyclocondensation of arylidene of quinazoline derivative with heterocyclic amines. Also, dibenzo[b,e][1,4]thiazepine derivatives was synthesized through the reaction of 2,6-bis-(2-chloro-benzylidene)-cyclohexanone with o-aminothiophenol. RESULTS: The structures of all new synthesized heterocyclic compounds were confirmed and discussed on the bases of spectral data. The utility of the preparation and design of the above mentioned compounds has been shown to be clear in the results of their antimicrobial activity which revealed that some derivatives have potent activity exceeding or similar to the activity of the reference drugs. CONCLUSION: The insertion of triazole or thiazole moieties to be fused with quinazoline ring helps to enhance its antimicrobial activity.


Assuntos
Quinazolinas/química , Quinazolinas/síntese química , Quinazolinas/farmacologia , Tiazepinas/química , Tiazepinas/síntese química , Tiazepinas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Azóis/síntese química , Azóis/química , Azóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
13.
Arch Pharm (Weinheim) ; 353(1): e1900211, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31696968

RESUMO

N-Substituted isatoic anhydrides were used as starting materials for the synthesis of compounds 5-16 through alkali hydrolysis, Schiff base reactions, and oxidation. Compounds 18-23 were obtained by thionation of their oxo isosteres using Lawesson's reagent. Cyclocondesation of anthranilic acid with thiourea afforded compounds 25-27, which were S-alkylated to afford compounds 28-30, which were thionated using Lawesson's reagent to afford 31-33. The compounds were tested for their in vitro inhibitory activity against the phosphodiesterase 7A (PDE7A) enzyme compared with the selective PDE7 inhibitor BRL50481. All the compounds showed the inhibitory activity on the enzyme at micromolar levels. Compounds 9 and 25 showed the highest inhibitory activity on the enzyme: IC50 = 0.096 and 0.074 µM, respectively, comparable to BRL50481 (IC50 = 0.072 µM). The binding mode and binding affinity of the target compounds at the enzyme PDE7A-binding site were studied through molecular docking. Compounds 9 and 25 showed good recognition at the enzyme-binding site and were capable of binding in an inhibitory mode similar to the reference compound BRL50481, forming the necessary interactions with the key amino acids. Docking studies and enzyme assay were in agreement.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Quinazolinas/farmacologia , Quinazolinonas/farmacologia , Tionas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/química
14.
Drug Des Devel Ther ; 13: 3079-3089, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695326

RESUMO

Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia. Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound. Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 µM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 µM against A549 cells, 2.46 and 1.35 µM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results. Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Células A549 , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Hipóxia Celular , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células HT29 , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nitroimidazóis/síntese química , Nitroimidazóis/química , Nitroimidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
15.
Chem Res Toxicol ; 32(11): 2238-2249, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31647221

RESUMO

Malassezia furfur isolates from diseased skin preferentially biosynthesize compounds which are among the most active known aryl-hydrocarbon receptor (AhR) inducers, such as indirubin, tryptanthrin, indolo[3,2-b]carbazole, and 6-formylindolo[3,2-b]carbazole. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carbaldehyde (I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for the biosynthesis of the alkaloids. Treatment of I3A with H2O2 and use of catalysts like diphenyldiselenide resulted in the simultaneous one-step transformation of I3A to indirubin and tryptanthrin in good yields. The same reaction was first applied on simple indole and then on substituted indoles and indole-3-carbaldehydes, leading to a series of mono- and bisubstituted indirubins and tryptanthrins bearing halogens, alkyl, or carbomethoxy groups. Afterward, they were evaluated for their AhR agonist activity in recombinant human and mouse hepatoma cell lines containing a stably transfected AhR-response luciferase reporter gene. Among them, 3,9-dibromotryptanthrin was found to be equipotent to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an AhR agonist, and 3-bromotryptanthrin was 10-times more potent than TCDD in the human HG2L7.5c1 cell line. In contrast, 3,9-dibromotryptanthrin and 3-bromotryptanthrin were ∼4000 and >10,000 times less potent than TCDD in the mouse H1L7.5c3 cell line, respectively, demonstrating that they are species-specific AhR agonists. Involvement of the AhR in the action of 3-bromotryptanthrin was confirmed by the ability of the AhR antagonists CH223191 and SR1 to inhibit 3-bromotryptanthrin-dependent reporter gene induction in human HG2L7.5c1 cells. In conclusion, I3A can be the starting material used by Malassezia for the production of both indirubin and tryptanthrin through an oxidation mechanism, and modification of these compounds can produce some highly potent, efficacious and species-selective AhR agonists.


Assuntos
Alcaloides/síntese química , Biomimética/métodos , Indóis/química , Malassezia/metabolismo , Quinazolinas/síntese química , Receptores de Hidrocarboneto Arílico/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Peróxido de Hidrogênio/farmacologia , Indóis/síntese química , Indóis/farmacologia , Malassezia/crescimento & desenvolvimento , Estrutura Molecular , Quinazolinas/química , Quinazolinas/farmacologia
16.
Carbohydr Res ; 486: 107832, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622868

RESUMO

Quinazolines were surveyed as biologically relevant moieties against different cancer cell lines, so in the present study, we analyzed novel derivatives as target-oriented chemotherapeutic anti-cancer drugs. A series of 3-substituted 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 4a-e were synthesized via the reaction of 2-aminobenzoic acid (1) with isothiocyanate derivatives 2a-e. S-alkylation and S-glycosylation were carried via the reaction of 4a-e with alkyl halides and α-glycopyranosyl bromides 7a,b under anhydrous alkaline and glycoside conditions, respectively. The S-alkylated and S-glycosylated structures, and not that of the N-alkylated and N-glycosylated isomers, have been selected for the products. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (DQF-COSY, HMQC, and HMBC). The S site of alkylation and glycosylation were determined from the 1H, 13C heteronuclear multiple-quantum coherence (HMQC) experiments. All derivatives were subjected to molecular docking calculations, which selected some derivatives (5n, 8c, 8g, 9c, and 9a) as promising ones based on their excellent binding affinities towards the EGFR tyrosine kinase molecular target. The in vitro cytotoxic activity against MCF-7 and HepG2 cell lines showed effective anti-proliferative activity of the analyzed derivatives with lower IC50 values especially 9a with IC50 = 2.09 and 2.08 µM against MCF-7 and HepG2, respectively, and their treatments were safe against the normal cell line Gingival mesenchymal stem cells (GMSC). Moreover, RT-PCR reaction investigated the apoptotic pathway for the compound 9a, which activated the P53 genes and its related genes. So, further work is recommended for developing it as a chemotherapeutic drug.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Quinazolinas/síntese química , Quinazolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/química , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Células MCF-7 , Conformação Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
17.
J Enzyme Inhib Med Chem ; 34(1): 1668-1677, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530043

RESUMO

Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
Bioorg Med Chem ; 27(20): 114938, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31488358

RESUMO

4-Anilinoquinazoline derivatives function as tyrosine kinase inhibitors (TKIs). Novel TKIs are needed for cancer mutations and drug-resistant cells. We designed and synthesized 4-anilinoquinazoline derivatives with substitutions at quinazoline positions 6, 7 and 4 using a binding model with multi-target receptor tyrosine kinases, and assessed their antitumor activity against five human tumor cell lines (HepG2, A549, MCF-7, DU145, SH-SY5Y). The majority of the compounds inhibited the proliferation of all the cancer cell types, with some compounds displaying selective inhibition. Compounds 21, 25, 27, and 37 displayed IC50 values of 7.588, 8.619, 6.936, and 8.516 µM, respectively, for A549 cells, which were much lower than that of Gefitinib (14.803 µM). Compound 32 displayed an IC50 value of 2.756 µM for DU145 cells. The representative compound 40 had unexceptionable broad-spectrum inhibition for all cancer cell types, and demonstrate inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-ß), and epidermal growth factor receptor (EGFR) with IC50 values of 46.4, 673.6 and 384.8 nM, respectively, which were similar to those of Sorafenib for VEGFR-2 and PDGFR-ß (140.6 and 582.7 nM, respectively). Molecular docking results supported the molecular level assay results. Data for production of reactive oxygen species and assessment of matrix metalloproteinase corroborated the strong anti-proliferative effect of compound 40. The compound also displayed robust antitumor efficacy and relativity lower toxicity in a xenograft model. These attributes were similar to those of Sorafenib. Compound 40 drug warrants further study as a candidate.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Espécies Reativas de Oxigênio/análise , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
19.
Future Med Chem ; 11(21): 2821-2830, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510797

RESUMO

Background: Gefitinib and sorafenib have been proved effective for the treatment of cancers in clinical practice for years. Materials & methods: We intended to integrate the structural features of gefitinib and sorafenib and construct structurally unique 7-aromatic ureido-4-anilinoquinazolines. Results: Most of the targets exhibited promising antitumor activities. 8u showed excellent antitumor activities against the three tested cell lines (IC50, 0.81-2.49 µM). The enzymatic, apoptosis assay of 8u were also performed to study their preliminary action of mechanism. Conclusion: 8u deserve further research as antitumor agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Ureia/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinazolinas/síntese química
20.
Bioorg Med Chem Lett ; 29(18): 2695-2699, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378571

RESUMO

We screened a series of 4-anilinoquinolines and 4-anilinoquinazolines and identified novel inhibitors of Mycobacterium tuberculosis (Mtb). The focused 4-anilinoquinoline/quinazoline scaffold arrays yielded compounds with high potency and the identification of 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (34) with an MIC90 value of 0.63-1.25 µM. We also defined a series of key structural features, including the benzyloxy aniline and the 6,7-dimethoxy quinoline ring, that are important for Mtb inhibition. Importantly the compounds showed very limited toxicity and scope for further improvement by iterative medicinal chemistry.


Assuntos
Compostos de Anilina/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Quinazolinas/farmacologia , Quinolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
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