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1.
Molecules ; 29(4)2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38398626

RESUMEN

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021-2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Diseño de Fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Quinasas/metabolismo , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular
2.
Bioorg Chem ; 142: 106920, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37898082

RESUMEN

In the current investigation, a new class of quinazolinone N-acetohydrazides 9a-v was designed as type II multi-kinase inhibitors. The target quinazolinones were tailored so that the quinazolinone moiety would occupy the front pocket of the binding sites of VEGFR-2, FGFR-1 and BRAF kinases, meanwhile, the phenyl group at position 2 would act as a spacer which was functionalized at position 4 with an N-acetohydrazide linker that could achieve the key interactions with the essential gate area amino acids. The hydrazide moiety was linked to diverse aryl derivatives to occupy the hydrophobic back pocket of the DFG-out conformation of target kinases. The synthesized quinazolinone derivatives 9a-v demonstrated moderate to potent VEGFR-2 inhibitory activity with IC50 spanning from 0.29 to 5.17 µM. Further evaluation of the most potent derivatives on FGFR-1, BRAFWT and BRAFV600E showed that the quinazolinone N-acetohydrazides 9d, 9e, 9f, 9l and 9m have a potent multi-kinase inhibitory activity. Concurrently, 9b, 9d, 9e, 9k, 9l, 9o, 9q demonstrated potent growth inhibitory activity on NCI cancer cell lines with GI50 reaching 0.72 µM. In addition, compound 9e arrested the cell cycle progression in MDA-MB-231 cell line at the G2/M phase and showed the ability to induce apoptosis.


Asunto(s)
Antineoplásicos , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Estructura Molecular , Relación Estructura-Actividad , Quinazolinonas/farmacología , Proteínas Proto-Oncogénicas B-raf , Inhibidores de Proteínas Quinasas , Proliferación Celular , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular
3.
Molecules ; 28(19)2023 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-37836657

RESUMEN

Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran-pyrazole-pyridine-based compound 8 with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound 8. The biological assays indicated that compound 8 produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound 8 is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials.


Asunto(s)
Benzofuranos , Osteoartritis , Humanos , Ratas , Animales , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/química , Pirazoles/farmacología , Pirazoles/uso terapéutico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico
4.
Eur J Med Chem ; 260: 115766, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37678141

RESUMEN

A series of novel benzofuran-based compounds 7a-s were designed, synthesized, and investigated in vitro as acetylcholinesterase inhibitors (AChEIs). Compounds 7c and 7e displayed promising inhibitory activity with IC50 values of 0.058 and 0.086 µM in comparison to donepezil with an IC50 value of 0.049 µM. The new molecules' antioxidant evaluation revealed that 7c, 7e, 7j, 7n, and 7q produced the strongest DPPH scavenging activity when compared to vitamin C. As it was the most promising AChEI, compound 7c was selected for further biological evaluation. Acute and chronic toxicity studies exhibited that 7c showed no signs of toxicity or adverse events, no significant differences in the blood profile, and an insignificant difference in hepatic enzymes, glucose, urea, creatinine, and albumin levels in the experimental rat group. Furthermore, 7c did not produce histopathological damage to normal liver, kidney, heart, and brain tissues, ameliorated tissue malonaldehyde (MDA) and glutathione (GSH) levels and reduced the expression levels of the APP and Tau genes in AD rats. Molecular docking results of compounds 7c and 7e showed good binding modes in the active site of the acetylcholinesterase enzyme, which are similar to the native ligand donepezil. 3D-QSAR analysis revealed the importance of the alkyl group in positions 2 and 3 of the phenyl moiety for the activity. Overall, these findings suggested that compound 7c could be deemed a promising candidate for the management of Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Benzofuranos , Animales , Ratas , Inhibidores de la Colinesterasa/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Donepezilo , Acetilcolinesterasa , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Benzofuranos/farmacología , Glutatión
5.
RSC Adv ; 13(27): 18496-18510, 2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37346948

RESUMEN

New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC50 value of 0.802 µM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil.

6.
Molecules ; 27(15)2022 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-35956876

RESUMEN

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35-8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.


Asunto(s)
Antineoplásicos , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Quinoxalinas/química , Relación Estructura-Actividad
7.
Bioorg Chem ; 111: 104827, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33798845

RESUMEN

A new set of derivatives bearing pyrazole-methylenehydrazono-thiazolidinone scaffold 4-23 was designed, synthesized and confirmed by different spectroscopic means and elemental analyses. In-vivo anti-inflammatory and ulcerogenic evaluation was performed for all the newly synthesized derivatives using indomethacin, celecoxib and diclofenac as standard drugs. The compounds 5, 10, 15, 17, 21, 22 appeared to be the most promising candidates producing rapid onset and long duration of anti-inflammatory activity as well as promising GIT safety profile. Furthermore, analgesic evaluation revealed that the compounds 5, 10, 15 and 22 produced potent and long acting analgesia accompanied with significant inhibition of the inflammatory cytokine TNF-α level in comparison with the standard drugs. Molecular docking study of the latter derivatives was also carried out to rationalize their binding affinities and their modes of interactions with the active site of TNF-α.


Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Pirazoles/farmacología , Tiazolidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiulcerosos/síntesis química , Antiulcerosos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Femenino , Hemorragia Gastrointestinal/tratamiento farmacológico , Hemorragia Gastrointestinal/metabolismo , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiazolidinas/química , Factor de Necrosis Tumoral alfa/metabolismo
8.
Molecules ; 26(8)2021 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-33919867

RESUMEN

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r2 = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ΔG of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an IC50 of 0.0136 µM, 0.015 µM, and 0.054 µM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 µM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. 131I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i. 131I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.


Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Descubrimiento de Drogas , Radioisótopos de Yodo/química , Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa , Células A549 , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Células CHO , Muerte Celular/efectos de los fármacos , Cumarinas/química , Cricetulus , Quinasa 2 Dependiente de la Ciclina/química , Quinasa 4 Dependiente de la Ciclina/química , Quinasa 4 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Simulación del Acoplamiento Molecular , Distribución Tisular/efectos de los fármacos
9.
RSC Adv ; 11(58): 36989-37010, 2021 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-35494381

RESUMEN

The current work represents the design and synthetic approaches of a new set of compounds 6-10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold. The biological evaluation revealed that most of the new compounds were promising selective dipeptidyl peptidase-IV (DPP-4) inhibitors and in vivo hypoglycemic agents utilizing linagliptin as a standard drug. The acute toxicity examination confirmed the safety profile of all compounds. Molecular docking studies related the significant DPP-4 suppression activity of compounds 9a, 10a, 10f, 10g to their nice fitting in the active pocket of DPP-4. In addition, the molecular dynamic study exhibited the stability of both 10a and 10g within the active site of DPP-4. The QSAR study showed that the difference between the predicted activities is very close to the experimental suppression effect. Moreover, both compounds 10a and 10g obeyed Lipinski's rule, indicating their efficient oral bioavailability. Compound 10a was radiolabeled, forming the 131I-SQ compound 10a to study the pharmacokinetic profile of this set of compounds. The biodistribution pattern hit the target protein since the tracer accumulated mainly in the visceral organs where DPP-4 is secreted in a high-level, thus with consequent stimulation of insulin secretion, leading to the target hypoglycemic effect.

10.
RSC Adv ; 12(1): 561-577, 2021 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-35424523

RESUMEN

Deregulation of various protein kinases is considered as one of the important factors resulting in cancer development and metastasis, thus multi-targeting the kinase family is one of the most important strategies in current cancer therapy. This context represents the design and synthesis of two sets of derivatives bearing a pyrazoline-3-one ring conjugated either with a thieno[3,2-d]thiazole or with a dihydrothiazolo[4,5-d]thiazole scaffold via an NH linker, 3a-d and 5a-d respectively, using the pyrazolinone-thiazolinone derivative 1 as a key precursor. All the newly synthesized compounds were assessed in vitro for their anticancer activity against two cancer cell lines (MCF-7 and HepG-2). The safety profile of the most active cytotoxic candidates 1 and 3c was further examined against the normal cell line WI-38. The compounds 1 and 3c were further evaluated as multi-targeting kinase inhibitors against EGFR, VEGFR-2 and BRAFV600E, exhibiting promising suppression impact. Additionally, the latter compounds were investigated for their impact on cell cycle and apoptosis induction potential in the MCF-7 cell line. Moreover, the antimicrobial activity of all the new analogues was evaluated against a panel of Gram-positive and Gram-negative bacteria, yeast and fungi in comparison to streptomycin and amphotericin-B as reference drugs. Interestingly, both 1 and 3c showed the most promising microbial inhibitory effect. Molecular docking studies showed promising binding patterns of the compounds 1 and 3c with the prospective targets, EGFR, VEGFR-2 and BRAFV600E. Finally, additional toxicity studies were performed for the new derivatives which showed their good drug-like properties and low toxicity risks in humans.

11.
Bioorg Med Chem ; 28(18): 115657, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32828424

RESUMEN

Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.


Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/química , Neoplasias de la Mama/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Tiazoles/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bencimidazoles/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Clorhidrato de Erlotinib/farmacología , Femenino , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad Cuantitativa , Tiazoles/farmacología
12.
Molecules ; 24(13)2019 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-31261939

RESUMEN

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8-5.7 nm) of the previously prepared benzofuran-pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP.


Asunto(s)
Benzofuranos/síntesis química , Neoplasias de la Mama/enzimología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Pirazoles/síntesis química , Benzofuranos/química , Benzofuranos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dispersión Dinámica de Luz , Femenino , Humanos , Células MCF-7 , Microscopía Electrónica de Transmisión , Nanopartículas , Tamaño de la Partícula , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Pirazoles/química , Pirazoles/farmacología
13.
Bioorg Chem ; 89: 103035, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31200286

RESUMEN

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzofuranos/química , Benzofuranos/farmacología , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Células HeLa , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Tiazolidinedionas/química , Tiazolidinedionas/farmacología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
14.
Bioorg Chem ; 86: 80-96, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30685646

RESUMEN

Motivated by the potential anticancer activity of both coumarin and 2-aminothiazole nuclei, a new set of thiazol-2-yl hydrazono-chromen-2-one analogs were efficiently synthesized aiming to obtain novel hybrids with potential cytotoxic activity. MTT assay investigated the significant potency of all the target compounds against the human cervical cancer cell lines (HeLa cells). Cell cycle analysis showed that the representative compound 8a led to cell cycle cessation at G0/G1 phase indicating that CDK2/E1complex could be the plausible biological target for these newly synthesized compounds. Thus, the most active compounds (7c and 8a-c) were tested for their CDK2 inhibitory activity. The biological results revealed their significant CDK2 inhibitory activity with IC50 range of 0.022-1.629 nM. Moreover, RT-PCR gene expression assay showed that compound 8a increased the levels of the nuclear CDK2 regulators P21 and P27 by 2.30 and 5.7 folds, respectively. ELISA tequnique showed also that compound 8a led to remarkable activation of caspases-9 and -3 inducing cell apoptosis. QSAR study showed that the charge distribution and molecular hydrophobicity are the structural features affecting cytotoxic activity in this series. Molecular docking study for the most potent cytotoxic compounds (7c and 8a-c) rationalized their superior CDK2 inhibitory activity through their hydrogen bonding and hydrophobic interactions with the key amino acids in the CDK2 binding site. Pharmacokinetic properties prediction of the most potent compounds showed that the newly synthesized compounds are not only with promising antitumor activity but also possess promising pharmacokinetic properties.


Asunto(s)
Antineoplásicos/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad Cuantitativa , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cumarinas/química , Cumarinas/farmacología , Quinasa 2 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Tiazoles/química , Tiazoles/farmacología , Células Tumorales Cultivadas
15.
Molecules ; 23(12)2018 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-30477238

RESUMEN

A series of novel 1,3,4-triarylpyrazoles containing different heterocycles has been prepared, characterized and screened for their in vitro antiproliferative activity against HePG-2, MCF-7, PC-3, A-549 and HCT-116 cancer cell lines. The biological results revealed that compound 6 showed the highest anticancer activity so it was subjected to a kinase assay study where it reduced the activity of several protein kinases including AKT1, AKT2, BRAF V600E, EGFR, p38α and PDGFRß at 100 µM using the radiometric or ADP-Glo assay method. Molecular docking simulation supported the initial kinase assay and suggested a common mode of interaction at the ATP-binding sites of these kinases, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further research.


Asunto(s)
Antineoplásicos/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Antineoplásicos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ligandos , Espectroscopía de Resonancia Magnética , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Relación Estructura-Actividad Cuantitativa
16.
Bioorg Chem ; 81: 481-493, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30243239

RESUMEN

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I-substrate in the pancreas and rapid clearance from most of the body organs.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Hipoglucemiantes/uso terapéutico , Sulfonamidas/uso terapéutico , Tetrahidronaftalenos/uso terapéutico , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Ratas , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/farmacología , Distribución Tisular
17.
Future Med Chem ; 10(2): 157-181, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29235906

RESUMEN

AIM: Synthesis of novel glutathione S-transferases (GSTs) inhibitors constitutes a promising strategy in cancer treatment. Results & methodology: A new set of benzimidazoles clubbed with various heterocycles as GST inhibitors and anticancer agents were synthesized. The biological results proved the potential of the new compounds as GST inhibitors, specifically compounds 7 and 14 which produced more potency than ethacrynic acid by three- and tenfold, respectively. Most compounds exhibited promising cytotoxic activity against breast and colon cancer cell lines. Molecular modeling studies revealed that compounds 7 and 14 showed good binding with the amino acids of the GST protein. CONCLUSION: Both compounds 7 and 14 fulfilled the Lipinski's rule of five suggesting them as new promising GST inhibitors and anticancer agents.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular
18.
Molecules ; 22(11)2017 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-29072621

RESUMEN

A new series of 2-alkyloxy-pyridine-3-carbonitrile-benzofuran hybrids (4a-x) was synthesized. All the new derivatives were examined via the standard technique for their vasodilation activity. Some of the investigated compounds exhibited a remarkable activity, with compounds 4w, 4e, 4r, 4s, 4f and 4g believed to be the most active hits in this study with IC50 values 0.223, 0.253, 0.254, 0.268, 0.267 and 0.275 mM, respectively, compared with amiodarone hydrochloride, the reference standard used (IC50 = 0.300 mM). CODESSA PRO was employed to obtain a statistically significant 2-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) model describing the bioactivity of the newly synthesized analogs (N = 24, n = 4, R² = 0.816, R²cvOO = 0.731, R²cvMO = 0.772, F = 21.103, s² = 6.191 × 10-8).


Asunto(s)
Benzofuranos/química , Técnicas de Química Sintética , Relación Estructura-Actividad Cuantitativa , Vasodilatadores/química , Animales , Aorta/efectos de los fármacos , Benzofuranos/síntesis química , Benzofuranos/farmacología , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Ratas , Vasodilatadores/síntesis química , Vasodilatadores/farmacología
19.
Acta Pol Pharm ; 74(3): 849-860, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-29513954

RESUMEN

The present study investigates, the synthesis of new derivatives of benzenesulfonamide nucleus hybridized with various substituted pyrazole 4, 8 and thiazole ring 6 using 4-amino-N-butylbenzenesulfonamide 1 as the key starting compound. Furthermore, 3,5-diaminopyrazole derivative 10 was allowed to react with different reagents such as an active methylene compounds, ketone dithioacetal, ethoxymethylene malononitrile and cyanoguanidine for a preparation of new benzenesulfonamide derivatives 11-18 conjugated with different substituted hetero-bicyclic ring systems. In vitm-antimicrobial evaluation was performed for most of the newly synthesized compounds using ciprofloxacin and Fluconazole as antibacterial and antifungal standard drugs, respectively The most promising dual antibacterial and antifungal potency was gained by the sulfamoylphenyl butenoic acid derivative 7, followed by the sulfamoylphenyl-2-chloroacetamide 5 and its heterocyclic pyrazolopyrimidine derivative 16. Further development and structural optimization will be carried out to get new more potent and safer antimicrobials.


Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Pruebas Antimicrobianas de Difusión por Disco , Descubrimiento de Drogas/métodos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Viabilidad Microbiana/efectos de los fármacos , Estructura Molecular , Relación Estructura-Actividad , Tecnología Farmacéutica/métodos
20.
Bioorg Med Chem Lett ; 26(10): 2557-2561, 2016 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-27048942

RESUMEN

Reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a-c with malononitrile in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol proceeds in a regioselective manner to afford 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-pyridinecarbonitriles 4-37, which also obtained by treating ylidenemalononitriles 6a-q with 2-acetylbenzofuran 1 in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol. The new chemical entities showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 11, 16, 21, 24 and 30 exhibited remarkable activity compared with amiodarone hydrochloride the reference standard used in the present study. CODESSA-Pro software was employing to obtain a statistically significant QSAR model describing the bioactivity of the newly synthesized analogs (N=31, n=5, R(2)=0.846, R(2)cvOO=0.765, R(2)cvMO=0.778, F=27.540. s(2)=0.002).


Asunto(s)
Benzofuranos/química , Piridinas/química , Relación Estructura-Actividad Cuantitativa , Vasodilatadores/química , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Benzofuranos/farmacología , Técnicas de Química Sintética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Piridinas/farmacología , Ratas , Vasodilatación/efectos de los fármacos
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