RESUMO
A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/análise , Antineoplásicos/síntese química , Antineoplásicos/química , Bioensaio , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/química , Quinazolinas/análise , Quinazolinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Carbonic anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10-29, 31, 32, 35, 36, and 45-51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14, 15, 17, 19, 20, 21, 24, 25, 28, 29, 31, 35, 45, 47, 49, and 51 with inhibition constant (KIs) values of 39.4-354.7â¯nM that were nearly equivalent or even greater than that of AAZ (KI, 250.0â¯nM). Compounds 15, 20, 24, 28, 29, 45 and 47 proved to have inhibitory activities against hCA II with (KIs, 0.73-16.5â¯nM) that were similar or improved to that of AAZ (KI, 12.0â¯nM). Compounds 13-29, 31-32, and 45-51 displayed potent hCA IX inhibitory activities (KIs, 1.6-32.2â¯nM) that were more effective than or nearly equal to AAZ (KI, 25.0â¯nM). Compounds 14, 15, 20, 21, 26, 45, and 47 exerted potent hCA XII inhibitory activities (KIs, 5.2-9.2â¯nM), indicating similar CAI activities as compared to that of AAZ (KI, 5.7â¯nM).
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Quinazolinas/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Quinazolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
A series of sulfonamides was obtained by reacting substituted-2-(1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxamido)benzoic acids with aromatic sulfonamides incorporating primary amino moieties. The new compounds were investigated as inhibitor of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I and II, and the α- and ß-class CAs from the pathogenic bacterium Vibrio cholerae, VchCAα and VhcCAß. hCA I was effectively inhibited by the new sulfonamides, with inhibition constants in the range of 4.9-96.0nM. hCA II also showed high affinity for these compounds (KIs of 2.1-22.3nM), whereas the two bacterial enzymes were less effectively inhibited, with KIs of 281-3192nM for VchCAα, and 5.40-9.26µM for VhcCAß. As the physiological function hCA I is poorly understood, and it was recently shown to be involved in the pathogenesis of cerebral malaria and amyotrophic lateral sclerosis, selective and effective inhibitors may be useful as tools or drugs for better understanding this abundant isoform.
Assuntos
Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Ftalimidas/química , Sulfonamidas/farmacologia , Vibrio cholerae/enzimologia , Inibidores da Anidrase Carbônica/química , Humanos , Sulfonamidas/químicaRESUMO
A new series, 2-substituted mercapto-3-[2-(pyridin-2-yl)ethyl]-4(3H)-quinazolinone 1-21, was synthesized and evaluated for in vivo anti-inflammatory and analgesic activities and in vitro COX-1/COX-2 inhibition. Compounds 1, 4, 5, 6, 8, 10, 13, 14, 15, 16, and 17 exhibited potent anti-inflammatory and analgesic properties, with ED50 values of 50.3-112.1mg/kg and 12.3-111.3mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED50=112.2 and 100.4mg/kg) and celecoxib (ED50=84.3 and 71.6mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC50 (0.33µM and 0.40µM, respectively) and selectivity index (SI>303.0 and >250.0, respectively) values that are similar to those of the reference drug celecoxib (IC50 0.30µM and COX-2 SI>333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC50 values of 0.70-0.80µM and COX-2 SI>125-142. Potent COX-2 inhibitors, such as compounds 4, 6, and 13, were docked into the active site pockets of COX-1 and COX-2, with the greatest recognition occurring at the COX-2 binding site and insignificant interactions at the binding site of the COX-1 pocket.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Desenho de Fármacos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Quinazolinonas/síntese química , Análise Espectral/métodosRESUMO
A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI(50) (10.47, 7.24 and 14.12 µM. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60 µM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.
Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , 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 , Proteínas Proto-Oncogênicas B-raf/metabolismo , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-AtividadeRESUMO
A series of benzenesulfonamides incorporating aroylhydrazone, piperidinyl, sulfone, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenyl-methylene)-1,3,4-thiadiazol-3(2H)-yl moieties was investigated as inhibitors of four α-carbonic anhydrases (CAs, EC 4.2.1.1), the human (h) isoforms hCA I, II (cytosolic, offtarget enzymes) and hCA IX and XII (transmembrane, tumor-associated isoforms). Low nanomolar activity was observed against hCA II (KIs of 0.56-17.1 nM) with these sulfonamides, whereas the slow cytosolic isoform hCA I was less inhibited by these compounds (KIs of 86.4 nM-32.8 µM). Most of these sulfonamides significantly inhibited CA IX, with KIs in the range of 4.5-47.0 nM, although some of the derivatives incorporating bulkier bicyclic moieties, as well as 2-thienyl fragments, showed a weaker activity against this isoform (KIs in the range 50.1-553 nM). All the investigated compounds also inhibited CA XII with KIs in the range 0.85-376 nM. The best inhibitors were those incorporating bulky [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl moieties and 1,3,4-thiadiazol-3(2H)-yl groups.
Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica II/química , Anidrase Carbônica I/química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Sulfonamidas/química , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/síntese química , Ensaios Enzimáticos , Humanos , Hidrazonas/química , Cinética , Piperidinas/química , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonas/química , Tiadiazóis/químicaRESUMO
A novel series of 2-(3-phenethyl-4(3H)quinazolin-2-ylthio)-N-substituted anilide and substituted phenyl 2-(3-phenethyl-4(3H) quinazolin-2-ylthio)acetate were designed, synthesized and evaluated for their in-vitro antitumor activity. Compound 15 possessed remarkable broad-spectrum antitumor activity which almost sevenfold more active than the known drug 5-FU with GI50 values of 3.16 and 22.60 µM, respectively. Compound 15 exhibited remarkable growth inhibitory activity pattern against renal cancer (GI50=1.77 µM), colon cancer (GI50=2.02 µM), non-small cell lung cancer (GI50=2.04 µM), breast cancer (GI50=2.77 µM), ovarian cancer (GI50=2.55 µM) and melanoma cancer (GI50=3.30 µM). Docking study was performed for compound 15 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib.
Assuntos
Anilidas/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinazolinas/farmacologia , Compostos de Sulfidrila/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
A novel series of 2-[(3-substituted-4(3H)-quinazolin-2-yl)thio]-N-(3,4,5-trimethoxyphenyl)acetamide (15-21) and 3-[(3-substituted-4(3H)-quinazolin-2-yl)thio])-N-(3,4,5-trimethoxyphenyl)propanamide (23-29) were designed, prepared and estimated for their anticancer activity in a solo dose 10 µM of the test compounds in the NCI 57 cell lines panel assay. Compounds 20, 23, 26, 27 and 28 revealed extensive-spectrum antitumor efficiency to numerous cell lines that belong to various tumor subpanels, while compounds 15, 16 and 19 possessed perceptive activity toward A498 and UO-31 renal cancer cell lines, and compound 17 showed selective effectiveness against NSC lung cancer NCI-H522 cell line. Additionally, compound 18 showed advanced activity against SR leukemia cell line, NSC lung cancer HOP-92 and renal cancer UO-31 cell lines.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Quinazolinonas/síntese química , Relação Estrutura-AtividadeRESUMO
A new series of substituted quinazolin-4-(3H)-one-tyrphostin derivatives was prepared and screened for their cytotoxic activity against three tumor cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using the colorimetric MTT assay. Among the current series, 10 compounds exhibited remarkable in vitro antiproliferative activity against the three tested cell lines with the IC(50) values ranging from 0.009 to 0.015 mM. All the compounds showed suitable drug like characteristics according to Lipinski's rule.