RESUMO
Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.
Assuntos
Restrição Calórica , Sirtuínas , Animais , Humanos , Síndrome de COVID-19 Pós-Aguda , Envelhecimento/metabolismo , Longevidade/fisiologia , Sirtuínas/metabolismo , Mamíferos/metabolismoRESUMO
As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Inflamatórios , Anti-Hipertensivos , Inibidores de Ciclo-Oxigenase 2 , Pirazóis , Tetrazóis , Pirazóis/farmacologia , Pirazóis/química , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/síntese química , Tetrazóis/farmacologia , Tetrazóis/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Ratos , Desenho de Fármacos , Masculino , Antifibróticos/farmacologia , Antifibróticos/química , Ciclo-Oxigenase 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Humanos , Peptidil Dipeptidase A/metabolismoRESUMO
A new series of nitric oxide-releasing estra-1,3,5,16-tetraene analogs (NO-∆-16-CIEAs) was designed and synthesized as dual inhibitors for EGFR and MRP2 based on our previous findings on estra-1,3,5-triene analog NO-CIEA 17 against both HepG2 and HepG2-R cell lines. Among the target compounds, 14a (R-isomer) and 14b (S-isomer) displayed potent anti-proliferative activity against both HepG2 and HepG2-R cell lines in comparison to the reference drug erlotinib. Remarkably, compound 14a resulted in a prominent reduction in EGFR phosphorylation at a concentration of 1.20 µM with slight activity on the phosphorylation of MEK1/2 and ERK1/2. It also inhibits MRP2 expression in a dose-dependent manner with 24% inhibition and arrested the cells in the S phase of the cell cycle. Interestingly, compound 14a (estratetraene core) exhibited a twofold increase in anti-proliferative activity against both HepG2 and HepG2-R in comparison with the lead estratriene analog, demonstrating the significance of the designed ∆-16 unsaturation. The results shed a light on compound 14a and support further investigations to combat multidrug resistance in chemotherapy of hepatocellular carcinoma patients.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Doadores de Óxido Nítrico/farmacologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/metabolismo , Óxido Nítrico/metabolismo , Receptores ErbB , Proliferação de Células , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
The quinoline scaffold has become an important construction motif for the development of new drugs. The quinolones and their heteroannulated derivatives have high importance due to their diverse spectrum of biological activities as antifungal, anti-inflammatory, anti-diabetes, anti-Alzheimer's disease, antioxidant and diuretic activities. This review summarizes the various new, efficient and convenient synthetic approaches to synthesize diverse quinolone-based scaffolds and their biological activities. We also dealt with the important mechanism, the route and type of reactions of the obtained products. The biological activities of some heteroannulated quinolones were also discussed.
Assuntos
Quinolonas , Antifúngicos , Quinolonas/farmacologiaRESUMO
The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.
Assuntos
Tratamento Farmacológico da COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , Aminas/farmacologia , Antivirais/química , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2RESUMO
Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure-activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein-ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea.
Assuntos
Quinolonas , Urease , Tioureia , Simulação de Acoplamento Molecular , Ligantes , Inibidores Enzimáticos/farmacologia , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Hidrazinas , Isotiocianatos , Estrutura MolecularRESUMO
Acetylcholinesterase (AChE) inhibitor and telomerase reverse transcriptase (TERT) potentiator phytochemicals are highly targeted as anti-Alzheimerês disease and as an anti-ageing process. A phytochemical study of Thunbergia erecta aerial parts resulted in the isolation of ten compounds (1-10). Their structures were identified based on spectral data and comparison with literature values. The activity of our pure isolates on AChE and TERT enzymes by documented in vitro assay methods were evaluated. The results indicated that apigenin (2), vanillic acid (4), and acacetin-7-O-ß-D-glucoside (7) exhibited potent inhibition of AChE (IC50 37.33, 30.80 and 49.57 ng/mL, respectively), compared to the standard drug donepezil (IC50 31.25 ng/mL). In the TERT enzyme assay, compound 7 triggered a 1.66fold increase in telomerase activity at the concentration of 2.85 ng/ml. This is the first study that demonstrates that compound 7 isolated from T. erecta can lead to such telomerase activity relative to control cells. Virtual screening studies including docking, rapid overlay chemical structure (ROCS), and calculated structure-property relationships (SPR) were implemented in this work. Molecular docking studies supported the binding of compounds 2, 4, and 7 through hydrogen bonds (HBs) formation to essential amino acid residues namely ARG:24 A, SER:347 A, LYS:51 A, PHE:346 A, and GLY:345 A of acetylcholinesterase. ROCS and SPR analyses realized compound 2 as a possible treatment of Alzheimer's disease and as a lead compound for drug development process through applying semisynthetic modifications.
Assuntos
Acanthaceae/química , Acetilcolinesterase/metabolismo , Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Electrophorus , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC50 ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G2/M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.HighlightsA novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.Compound 12c showed significant antiproliferative activities against different cancer cell lines.Compound 12c effectively inhibited tubulin polymerisation and competed with [3H] colchicine in binding to tubulin.Compound 12c arrested the cell cycle at G2/M phase, effectively inducing apoptosis and inhibition of cell migration.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Quinolinas/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Polimerização/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.
Assuntos
GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Desenho de Fármacos , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacologia , Piridinas/química , Tiazóis/química , Humanos , Relação Estrutura-AtividadeRESUMO
A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC50 values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Descoberta de Drogas , Inibidores da Fosfodiesterase 5/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 5/síntese química , Inibidores da Fosfodiesterase 5/química , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Two new series of hybrid structures 16a-f and 19a-f containing 1,2,4-triazole moiety, pyrazole core with COX-2 pharmacophore and oxime as NO donor moiety were designed, synthesized and evaluated for anti-inflammatory, cytotoxic activities and NO release. All compounds were more selective for COX-2 isozyme especially the sulphamoyl derivatives (16b, 16e, 19b and 19e) had COX-2 selectivity indexes (S.I. = 9.78, 8.57, 10.78 and 10.47 respectively) in comparison to celecoxib (S.I. = 8.68). Similarly, 16b, 16e, 19b and 19e were the most potent anti-inflammatory derivatives with ED50 = 46.98-54.45 µmol/kg better than celecoxib (ED50 = 76.09 µmol/kg). Also, 16b, 16e, 19b and 19e were significantly less ulcerogenic (ulcer indexes = 2.79-3.95) upon comparison with ibuprofen (ulcer index = 20.25) and comparable with celecoxib (ulcer index = 2.93). Regarding anti-cancer activity, most of the target derivatives 16a-f and 19a-f showed good activities against A-549, MCF-7, HCT-116 and PC-3 cancer cell lines. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The sulphamoyl derivatives with internal oxime 19b and 19e were the most potent derivatives against all used cell lines especially PC-3 (IC50 = 1.48 and 0.33 µM respectively) with 11.75 and 39.4-fold respectively selectivity towards PC-3 than F180 fibroblasts. The mechanistic investigation of 19b and 19e revealed that both compounds arrested cell cycle at G2/M phase by 32.16 and 39.95 folds, up-regulated Bax expression by 6.83 and 14.52 folds and down-regulated the expression of the gene Bcl-2 by 0.57 and 0.36fold respectively. Also, 19b and 19e were good inhibitor for p38MAPK (0.65 for 19b and 0.58 for 19e) and VEGFR-2 (0.39 for 19b and 0.54 for 19e) in comparison with PC-3 control cell. All compounds 16a-f and 19a-f released NO in a slow rate (0.15-3.17%) and the four sulphamoyl derivatives 16b, 16e, 19b and 19e were the most NO releasers (3.06, 2.15, 3.17 and 2.54% respectively). Docking studies were carried out to explain the interaction of 16a-f and 19a-f with the target enzymes. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding EGFR inhibition, docking was carried out with ID: 1M17. The internal oxime serious was more active as anticancer because of their ability to form extra HBs with receptor cleft.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Celecoxib/síntese química , Celecoxib/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/metabolismo , Oximas/química , Oximas/farmacologia , Células PC-3 , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Wistar , Úlcera Gástrica/tratamento farmacológico , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
New imidazolidindiones and tetra-substituted imidazole derivatives were designed, synthesized, and evaluated for the anticonvulsant activity through pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) tests using valproate sodium and phenytoin sodium as reference drugs, respectively. Most of the target compounds showed excellent activity against pentylenetetrazole (PTZ)-induced seizures with fair to no-activity against MES. Compounds 3d, 4e, 11b, and 11e showed higher activity (120%) than that of valproate sodium in PTZ model. Almost all compounds showed no neurotoxicity, as indicated by the rotarod test. Estimation of physicochemical properties and pharmacokinetic profiles of the target compounds were studied. The chemical structures of the target compounds were characterized by different spectrometric methods and elemental analysis.
Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Relação Dose-Resposta a Droga , Eletrochoque , Imidazóis/administração & dosagem , Imidazóis/síntese química , Camundongos , Teste de Desempenho do Rota-Rod , Relação Estrutura-AtividadeRESUMO
PDE5 targeting represents a new and promising strategy for apoptosis induction and inhibition of tumor cell growth due to its over-expression in diverse types of human carcinomas. Accordingly, we report the synthesis of series of pyrazolo[3,4-d]pyrimidin-4-one carrying quinoline moiety (11a-r) with potential dual PDE5 inhibition and apoptotic induction for cancer treatment. These hybrids were structurally elucidated and characterized with variant spectroscopic techniques as 1H NMR, 13C NMR and elemental analysis. The assessment of their anticancer activities has been declared. All the rationalized compounds 11a-r have been selected for their cytotoxic activity screening by NCI against 60 cell lines. Compounds 11a, 11b, 11j and 11k were the most active hybrids. Among all, compound 11j was further selected for five dose tesing and it displayed outstanding activity with strong antitumor activity against the nine tumor subpanels tested with selectivity ratios ranging from 0.019 to 8.3 at the GI50 level. Further, the most active targets 11a, b, j and k were screened for their PDE5 inhibitory activity, compound 11j (with IC50 1.57 nM) exhibited the most potent PDE5 inhibitory activity. Moreover, compound 11j is also showed moderate EGFR inhibition with IC50 of 5.827 ± 0.46 µM, but significantly inhibited the Wnt/ß-catenin pathway with IC501286.96 ± 12.37 ng/mL. In addition, compound 11j induced the intrinsic apoptotic mitochondrial pathway in HepG2 cells as evidenced by the lower expression levels of the anti-apoptotic Bcl-2 protein, and the higher expression of the pro-apoptotic protein Bax, p53, cytochrome c and the up-regulated active caspase-9 and caspase-3 levels. All results confirmed by western blotting assay. Compound 11j exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase. In conclusion, hybridization of quinoline moiety with the privileged pyrazolo[3,4-d]pyrimidinon-4-one structure resulted in highly potent anticancer agent, 11j, which deserves more study, in particular, in vivo and clinical investiagtions, and it is expected that these results would be applied for more drug discovery process.
Assuntos
Antineoplásicos/síntese química , Inibidores da Fosfodiesterase 5/síntese química , Quinolinas/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspases Efetoras/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocromos c/metabolismo , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolinas/farmacologia , Proteína X Associada a bcl-2/metabolismoRESUMO
Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class of nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget agents. Synthesized analogs were initially evaluated for their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 and 20a exhibited more potent activity against HepG2 cells (IC50â¯=â¯4.69 and 12.5⯵M, respectively) than the reference drug Erlotinib (IC50â¯=â¯25⯵M). Interestingly, NO-CIEA 17 exerted also a high potent activity against Erlotinib-resistant HepG2 cell line (HepG2-R) (IC50â¯=â¯8.21⯵M) giving insight about its importance in drug resistance therapy. Intracellular measurements of NO revealed that NO-CIEAs 17 and 20a showed a significant increase in NO production in tumor cells after 1â¯h of incubation comparable to the reference prodrug JS-K. Flow cytometric analysis showed that both NO-CIEAs 17 and 20a mainly arrested the HepG2 cells in the G0/G1 phase. Also, In-Cell Based ELISA screening showed that NO-CIEA 17 resulted in a potential inhibitory activity towards the EGFR and MAPK (25% and 29% inhibition compared to untreated control cells, respectively). This data suggests the binding ability of NO-CIEA 17 to the EGFR and ERK to be well correlated along with the docking and cellular studies. Also, treatment of HepG2-R cells with NO-CIEA 17 showed a potential reduction of MRP2 expression in a dose dependent manner providing a significant impact on the chemotherapeutic resistance. Overall, the current study provides a potential new approach for the discovery of a novel antitumor agent against HCC.
Assuntos
Antineoplásicos/farmacologia , Cucurbitacinas/farmacologia , Desenho de Fármacos , Estrona/análogos & derivados , Estrona/farmacologia , Doadores de Óxido Nítrico/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Hepatocelular/tratamento farmacológico , Cucurbitacinas/síntese química , Cucurbitacinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Estrona/síntese química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Relação Estrutura-AtividadeRESUMO
Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15â¯days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I.â¯=â¯8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activityâ¯=â¯62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activityâ¯=â¯49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activityâ¯=â¯53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.
Assuntos
Anti-Inflamatórios/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , PPAR gama/agonistas , Pirróis/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Domínio Catalítico , Celecoxib/química , Celecoxib/farmacologia , Celulases/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/efeitos adversos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/química , Pirróis/efeitos adversos , Pirróis/síntese química , Pirróis/química , Ratos , Ovinos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-Atividade , Tiazolidinas/efeitos adversos , Tiazolidinas/síntese química , Tiazolidinas/química , alfa-Glucosidases/metabolismoRESUMO
The designed compounds, 4a-p, were synthesized using a simple and smooth method with an asymmetric 1,3-dipolar reaction as the key step. The chemical structures for all synthesized compounds were elucidated and confirmed by spectral analysis. The molecular complexity and the absolute stereochemistry of 4b and 4e designed analogs were determined by X-ray crystallographic analysis. The anticancer activities of the synthesized compounds were tested against colon (HCT-116), prostate (PC-3), and hepatocellular (HepG-2) cancer cell lines. Molecular modeling revealed that the compound 4d binds through hydrophobic-hydrophobic interactions with the essential amino acids (LEU: 57, GLY: 58, ILE: 61, and HIS: 96) in the p53-binding cleft, as a standard p53-MDM2 inhibitor (6SJ). The mechanism underlying the anticancer activity of compound 4d was further evaluated, and the study showed that compound 4d inhibited colony formation, cell migration, arrested cancer cell growth at G2/M, and induced apoptosis through intrinsic and extrinsic pathways. Transactivation of p53 was confirmed by flow cytometry, where compound 4d increased the level of activated p53 and induced mRNA levels of cell cycle inhibitor, p21.
Assuntos
Desenho de Fármacos , Antineoplásicos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Oxindóis , Proteínas Proto-Oncogênicas c-mdm2 , Compostos de Espiro , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53RESUMO
Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50â¯=â¯1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50â¯=â¯247.14â¯nM and 208.42â¯nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds' activity.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Quinolonas/síntese química , Quinolonas/metabolismo , Relação Estrutura-AtividadeRESUMO
Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71-89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC50â¯=â¯7⯱â¯0.27⯵M, SI: 3.7), and HepG2 (IC50â¯=â¯5.5⯱â¯0.2⯵M, SI: 4.7) in comparison to (IC50â¯=â¯12.6⯱â¯0.5, SI: 0.4 and 5.5⯱â¯0.3⯵M, SI: 0.9, respectively). Compound 4k was less active (IC50â¯=â¯6⯱â¯0.3⯵M, SI: 4.3) than cisplatin (IC50â¯=â¯5⯱â¯0.56⯵M, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.
Assuntos
Antineoplásicos/farmacologia , Oxindóis/farmacologia , Pirrolidinas/farmacologia , Compostos de Espiro/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindóis/síntese química , Oxindóis/química , Oxindóis/toxicidade , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/toxicidade , Proteína Supressora de Tumor p53/metabolismo , Células VeroRESUMO
An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N'-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC50 = 5 ± 0.25 µM] > 3e [IC50 = 5 ± 0.5 µM] > 3c [IC50 = 7 ± 1.12 µM] > 3d [IC50 = 18 ± 0.87 µM] > 3j [IC50 = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC50 of 8 ± 0.76 and 14.7 ± 0.5 µM against HCT-116 and HuH-7 cells, respectively). The highest α-glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.
Assuntos
Amidas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Cicloexanonas/química , Cicloexanonas/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Piridinas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexanonas/síntese química , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , alfa-Glucosidases/químicaRESUMO
Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I.â¯=â¯9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50â¯=â¯15.06, 42.51 and 50.43⯵mol/kg respectively) in comparison with celecoxib (COX-2 S.I.â¯=â¯8.61, ED50â¯=â¯82.2⯵mol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexesâ¯=â¯2.72-3.72) than ibuprofen (ulcer indexâ¯=â¯20.25) and comparable to celecoxib (ulcer indexâ¯=â¯2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.