Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500603

RESUMO

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.


Assuntos
Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064806

RESUMO

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole-chalcone hybrids (1-20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC50 = 11 ± 1 µM) with an IC50 value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Chalconas/farmacocinética , Desenho de Fármacos , Simulação de Acoplamento Molecular , Tiazóis/farmacologia , Tiazóis/farmacocinética , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/química
3.
Polymers (Basel) ; 13(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805240

RESUMO

The non-toxic inorganic antimicrobial agents iodine (I2) and copper (Cu) are interesting alternatives for biocidal applications. Iodine is broad-spectrum antimicrobial agent but its use is overshadowed by compound instability, uncontrolled iodine release and short-term effectiveness. These disadvantages can be reduced by forming complex-stabilized, polymeric polyiodides. In a facile, in-vitro synthesis we prepared the copper-pentaiodide complex [Cu(H2O)6(12-crown-4)5]I6 · 2I2, investigated its structure and antimicrobial properties. The chemical structure of the compound has been verified. We used agar well and disc-diffusion method assays against nine microbial reference strains in comparison to common antibiotics. The stable complex revealed excellent inhibition zones against C. albicans WDCM 00054, and strong antibacterial activities against several pathogens. [Cu(H2O)6(12-crown-4)5]I6 · 2I2 is a strong antimicrobial agent with an interesting crystal structure consisting of complexes located on an inversion center and surrounded by six 12-crown-4 molecules forming a cationic substructure. The six 12-crown-4 molecules form hydrogen bonds with the central Cu(H2O)6. The anionic substructure is a halogen bonded polymer which is formed by formal I5- repetition units. The topology of this chain-type polyiodide is unique. The I5- repetition units can be understood as a triodide anion connected to two iodine molecules.

4.
Eur J Med Chem ; 219: 113442, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33878562

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) is becoming dangerous to human beings due to easy transmission mode and leading to the difficult-to-treat situation. The rapid resistance development of MRSA to many approved antibiotics is of major concern. There is a lot of scope to develop novel, efficient, specific, and nontoxic drug candidates to fight against MRSA isolates. The interesting molecular structure and adaptable feature of oxadiazole moiety which are bioisosteres of esters and amides, and these functional groups show improved resistance to esterases mediated hydrolytic cleavage, attracting researchers to develop required novel antibiotics based on oxadiazole core. This review summarizes the developments of oxadiazole-containing derivatives as potent antibacterial agents against multidrug-resistant MRSA strains and discussing the structure-activity relationship (SAR) in various directions. The current survey is the highlight of the present scenario of oxadiazole hybrids on MRSA studies, covering articles published from 2011 to 2020. This collective information may become a good platform to plan and develop new oxadiazole-based small molecule growth inhibitors of MRSA with minimal side effects.


Assuntos
Antibacterianos/farmacologia , Oxidiazóis/química , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Desenho de Fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxidiazóis/metabolismo , Oxidiazóis/farmacologia , Relação Estrutura-Atividade
5.
Pharmaceuticals (Basel) ; 13(11)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182305

RESUMO

Despite the availability of many drugs to treat infectious diseases, the problems like narrow antimicrobial spectrum, drug resistance, hypersensitivities and systemic toxicities are hampering their clinical utility. Based on the above facts, in the present study, we designed, synthesized and evaluated the antibacterial and antifungal activity of novel fluorinated compounds comprising of chalcones bearing trifluoromethyl (A1-A10) and trifluoromethoxy (B1-B10) substituents. The compounds were characterized by spectroscopic techniques and evaluated for their antimicrobial activity against four pathogenic Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Escherichia coli and Bacillus subtilis) bacterial and fungal (Candida albicans and Aspergillus niger) strains. In this study, the compounds with trifluoromethoxy group were more effective than those with trifluoromethyl group. Among the 20 fluorinated chalcones, compound A3/B3 bearing an indole ring attached to the olefinic carbon have been proved to possess the most antimicrobial activity compared to the standard drugs without showing cytotoxicity on human normal liver cell line (L02). Further, the minimum inhibitory concentration (MIC) for A3/B3 was determined by serial tube dilution method and showed potential activity. These results would provide promising access to future study about the development of novel agents against bacterial and fungal infections.

6.
Molecules ; 25(14)2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32668655

RESUMO

Infectious diseases caused by fungi and mycobacteria pose an important problem for humankind. Similarly, cancer is one of the leading causes of death globally. Therefore, there is an urgent need for the development of novel agents to combat the deadly problems of cancer, tuberculosis, and also fungal infections. Hence, in the present study, we designed, synthesized, and characterized 30 compounds including 15 chalcones (2-16) and 15 dihydropyrazoles (17-31) containing dichlorophenyl moiety and also screened these compounds for their antifungal, antitubercular, and antiproliferative activities. Among these compounds, the dihydropyrazoles showed excellent antifungal and antitubercular activities whereas the chalcones exhibited promising antiproliferative activity. Among the dihydropyrazoles, compound 31 containing 2-thienyl moiety showed promising antifungal activity (MIC 5.35 µM), whereas compounds 22 and 24 containing 2,4-difluorophenyl and 4-trifluoromethyl scaffolds revealed significant antitubercular activity with the MICs of 3.96 and 3.67 µM, respectively. Compound 16 containing 2-thienyl moiety in the chalcone series showed the highest anti-proliferative activity with an IC50 value of 17 ± 1 µM. The most active compounds identified through this study could be considered as starting points in the development of drugs with potential antifungal, antitubercular, and antiproliferative activities.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Pirazóis/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antituberculosos/síntese química , Antituberculosos/química , Aspergillus niger/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
7.
Molecules ; 25(5)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110945

RESUMO

Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (17-31) and 15 dihydropyrazoles (32-46) derived from these chalcones for their antimicrobial, antioxidant, and anticancer activities. Chalcones exhibited superior antibacterial and antioxidant activities compared to dihydropyrazoles. Among the chalcones, compound 28 showed potent antibacterial (MIC = 1 µg/mL) and antioxidant activities (IC50 = 5 ± 1 µg/mL). Dihydropyrazoles, on the contrary, demonstrated remarkable antifungal and anticancer activities. Compound 46 (IC50 = 2 ± 1 µg/mL) showed excellent antifungal activity whereas two other dihydropyrazoles 45 (IC50 = 2 ± 1 µg/mL) and 39 (IC50 = 4 ± 1 µg/mL) exhibited potential anticancer activity. The compounds were also tested for their toxicity on normal human cell lines (LO2) and were found to be nontoxic. The active compounds that have emerged out of this study are potential lead molecules for the development of novel drugs against infectious diseases, oxidative stress, and cancer.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Chalconas/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Pirazóis/farmacologia , Bactérias/efeitos dos fármacos , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Fungos/efeitos dos fármacos , Humanos , Isoxazóis/síntese química , Testes de Sensibilidade Microbiana , Picratos/química , Pirazóis/síntese química , Pirazóis/química
8.
Med Chem ; 10(4): 361-75, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24021160

RESUMO

Previous structure-activity relationship studies involving a series of lactone-based muscarinic ligands identified a lead compound containing a diphenylmethylpiperazine moiety (4; IC50 = 340 nM). The purpose of the present work is to investigate 1,3-benzodioxoles, 4,4-diethyl substituted tetrahydrofurans, 5-substituted oxazolidinones and chromones as bioisosteric replacements for the lactone ring in a novel series of muscarinic ligands. The approach provided compounds with improved % inhibition values and identified a non-selective muscarinic ligand with an IC50 value of 280 nM. The structure-activity relationship for this new series will be discussed. Selected compounds were evaluated in preliminary assays for subtype selectivity and were found to be non-selective.


Assuntos
Colinérgicos/farmacologia , Desenho de Fármacos , Lactonas/química , Piperazinas/farmacologia , Receptores Muscarínicos/metabolismo , Colinérgicos/síntese química , Colinérgicos/química , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...