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1.
Bioorg Chem ; 116: 105363, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34555629

RESUMO

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 µM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 µM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

2.
Bioorg Chem ; 116: 105302, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34464816

RESUMO

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19-31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82-1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes.

3.
Future Med Chem ; 13(18): 1559-1590, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34340532

RESUMO

FAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in which the kinase has been implicated in promoting metastases. Consequently, designing and developing potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as a promising tool in our armamentarium for treating diverse cancers. This review comprehensively summarizes the different classes of synthetically derived compounds that have been reported as potent FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed to slow down the emergence of drug resistance is discussed.

4.
Eur J Med Chem ; 222: 113569, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111829

RESUMO

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of both HDAC2 (IC50 = 0.09-1.40 µM) and FAK (IC50 = 12.59-36.11 nM); 6a revealed the highest activity with IC50 values of 0.09 µM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized by molecular docking. Taken together, these findings highlight the potential of 6a as a promising dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.


Assuntos
Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 1 de Adesão Focal/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais Cultivadas
5.
Bioorg Chem ; 106: 104422, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33248713

RESUMO

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC50 = 2.53, 2.01, 17.36, 12.23 and 3.1 µM for HCT-116 cells, respectively and IC50 = 0.73, 0.64, 3.32, 13.72 and 1.17 µM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIß with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3, -8, and -9), release of cytochrome C from mitochondria, upregulation of proapoptotic Bax and down-regulation of Bcl-2 protein level. Thus, the new ciprofloxacin derivative 3j could be considered as a potential lead for further optimization of antitumor agent against leukemia and colorectal carcinoma.

6.
Chem Biodivers ; 17(6): e2000100, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32239712

RESUMO

A facile and convenient synthesis of new pyridazines suitable for use as antimicrobial agents was reported. The hydrazide intermediate was coupled with various benzaldehydes and/or acetophenones and cyclized instantaneously to afford target pyridazine derivatives. The structures of new pyridazines were confirmed by IR, 1 H- and 13 C-NMR, elemental analysis in addition to representative LC/MS. Antimicrobial activity was screened against 10 bacterial and fungal strains. The new pyridazines showed strong to very strong antibacterial activity against Gram-negative (GNB) bacteria, while none of them showed significant antifungal activity at the same concentration range. Chloro derivatives exhibited the highest antibacterial activity with MICs (0.892-3.744 µg/mL) lower than that of chloramphenicol (2.019-8.078 µg/mL) against E. coli, P. aeruginosa, and S. marcescens. Prediction of ADME parameters, pharmacokinetics, and substrate promiscuity revealed that these new pyridazines could be promising drug candidates. Cytotoxic studies on rat hepatocytes showed how much safe these new pyridazines on living organisms (IC50 >64 µg/mL). MOE docking studies showed a good overlay of these new pyridazines with co-crystallized ligand within an E. coli DNA gyrase subunit B active sites (4KFG).


Assuntos
Anti-Infecciosos/síntese química , Simulação de Acoplamento Molecular , Piridazinas/química , Animais , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Sítios de Ligação , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , DNA Girase/química , DNA Girase/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Piridazinas/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Termodinâmica
7.
Bioorg Chem ; 91: 103132, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31374529

RESUMO

A new series of hybrid structures 14a-l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO2Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes = 2.64-3.87) than ibuprofen (ulcer index = 20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50 = 5.32-17.90, 3.67-19.04 and 3.19-14.87 µM respectively) in comparison with doxorubicin (IC50 = 0.20, 0.50 and 2.44 µM respectively). Compound 14a inhibited the human topoisomerase-1 with IC50 = 29.7 µg/ml while 14b and 14c showed more potent inhibitory activity with IC50 = 26.5 and 23.3 µg/ml. respectively in comparison with camptothecin (IC50 = 20.2 µg/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a-l with the target enzymes.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Tioidantoínas/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Tioidantoínas/síntese química , Tioidantoínas/metabolismo
8.
Bioorg Med Chem ; 23(17): 5681-92, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26211459

RESUMO

Steroid sulfatase (STS) catalyzes the hydrolysis of the sulfate ester group in biologically inactive sulfated steroids to give biologically active steroids. Inhibitors of STS are considered to be potential therapeutics for treating hormone-dependent cancers such as ER(+) breast cancer. A series of 4-substituted 17ß-arylsulfonamides of 17ß-aminoestra-1,3,5(10)-trien-3-ol were prepared and examined as STS inhibitors. The presence of a NO2 or Br at the 2-position of the A-ring resulted in a decrease in potency compared to their A-ring-unsubstituted counterparts. However the presence of a nitro group or fluorine atom at the 4-position of the A-ring resulted in an increase in potency and one of these compounds exhibited a Ki(app) value of 1 nM. Modeling studies provided insight into how these compounds interact with active site residues. The anti-proliferative activity of the 3'-Br, 3'-CF3, 4-NO2-3'-Br and 4-NO2-3'-CF3 derivatives were examined using the NCI 60-cell-line panel and found to have mean graph midpoint values of 1.9-3.4 µM.


Assuntos
Arilsulfatases/química , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Hormônios Esteroides Gonadais/efeitos adversos , Esteril-Sulfatase/antagonistas & inibidores , Sulfonamidas/química , Arilsulfatases/farmacologia , Humanos , Estrutura Molecular , Sulfonamidas/farmacologia
9.
J Steroid Biochem Mol Biol ; 137: 183-98, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23391659

RESUMO

Sulfated steroids function as a storage reservoir of biologically active steroid hormones. The sulfated steroids themselves are biologically inactive and only become active in vivo when they are converted into their desulfated (unconjugated) form by the enzyme steroid sulfatase (STS). Inhibitors of STS are considered to be potential therapeutics for the treatment of steroid-dependent cancers such as breast, prostate and endometrial cancer. The present review summarizes steroid derivatives as inhibitors of STS covering the literature from the early years of STS inhibitor development to October of 2012. A brief discussion of the function, structure and mechanism of STS and its role in estrogen receptor-positive (ER+) hormone-dependent breast cancer is also presented. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".


Assuntos
Inibidores Enzimáticos/farmacologia , Esteroides/farmacologia , Esteril-Sulfatase/antagonistas & inibidores , Neoplasias da Mama/enzimologia , Neoplasias do Endométrio/enzimologia , Feminino , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Esteril-Sulfatase/metabolismo , Especificidade por Substrato
10.
Bioorg Med Chem ; 20(4): 1535-44, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22264754

RESUMO

Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast and other steroid-dependent cancers. Here we report the synthesis of a series of 17ß-arylsulfonamides of 17ß-aminoestra-1,3,5(10)-trien-3-ol and their evaluation as inhibitors of STS. Some of these compounds are among the most potent reversible STS inhibitors reported to date. Introducing n-alkyl groups into the 4'-position of the 17ß-benzenesulfonamide derivative resulted in an increase in potency with the n-butyl derivative exhibiting the best potency with an IC(50) of 26 nM. A further increase in carbon units (to n-pentyl) resulted in a decrease in potency. Branching of the 4'-n-propyl group resulted in a decrease in potency while branching of the 4'-n-butyl group (to a tert-butyl group) resulted in a slight increase in potency (IC(50)=18 nM). Studies with 3'- and 4'-substituted substituted 17ß-benzenesulfonamides with small electron donating and electron withdrawing groups revealed the 3'-bromo and 3'-trifluoromethyl derivatives to be excellent inhibitors with IC(50)'s of 30 and 23 nM, respectively. The 17ß-2'-naphthalenesulfonamide was also an excellent inhibitor (IC(50)=20 nM) while the 17ß-4'-phenylbenzenesulfonamide derivative was the most potent inhibitor of all the compounds studied with an IC(50) of 9 nM.


Assuntos
Arilsulfatases/química , Esteril-Sulfatase/antagonistas & inibidores , Sulfonamidas/química , Arilsulfatases/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Sulfonamidas/farmacologia
11.
Arch Pharm Res ; 31(3): 279-93, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18409039

RESUMO

Certain new derivatives of 1,2,4-triazolo[1,5-a]pyrimidines were synthesized through the reaction of 1,2,4-triazolo[1,5-a]pyrimidine-7-ol with ethyl bromoacetate to afford the ethyl acetate ester, which upon hydrazinolysis gives the corresponding hydrazide. The hydrazide is the key intermediate which was used for the synthesis of the target compounds. The structures of the new compounds were assigned by spectral and elemental methods of analyses. The synthesized compounds were tested for their in vitro antibacterial and antifungal activities. Most of the tested compounds showed comparable results with those of ampicillin and fluconazole reference drugs.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fungos Mitospóricos/efeitos dos fármacos , Pirimidinas/farmacologia , Triazóis/farmacologia , Acetatos/química , Ampicilina/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Fluconazol/farmacologia , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Hidrocarbonetos Bromados/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Fungos Mitospóricos/crescimento & desenvolvimento , Estrutura Molecular , Pirimidinas/síntese química , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Triazóis/síntese química
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