RESUMO
A series of novel benzophenone derivatives containing a thiazole heterocyclic nucleus were designed by molecular hybridization. Molecular docking studies have demonstrated the inhibitory potential of the designed compounds against cyclooxygenase (COX) isoenzymes. These compounds were synthesized, characterized, and evaluated for their anti-inflammatory properties by the croton oil-induced ear edema assay to examine their effect on both prostaglandin (PG) production and neutrophils recruitment. The thiazole derivatives displayed a potent effect in terms of reducing ear edema. The analysis suggested that the presence of 4-phenyl-2-hydrazinothiazole and the absence of C4'-OCH3 on the benzophenone derivative structure are strongly related to the inhibition of PG production. In addition, the derivatives 2e, 3a and 3c concomitantly inhibit PG production and neutrophil recruitment, which may be a mechanism of action better than of common NSAIDs due to their inability to inhibit the neutrophil recruitment. Thus, these compounds can be considered as potential lead compounds toward the development of new anti-inflammatory drugs with an innovating mechanism of action.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Desenho de Fármacos , Edema/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Animais , Anti-Inflamatórios/síntese química , Benzofenonas/síntese química , Sítios de Ligação , Domínio Catalítico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/química , Modelos Animais de Doenças , Edema/tratamento farmacológico , Isomerismo , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC50 values in the nanomolar range. Cell cycle arrest in G2/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G2/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential.
Assuntos
Apoptose/efeitos dos fármacos , Benzofenonas/farmacologia , Divisão Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Moduladores de Tubulina , Tubulina (Proteína)/biossíntese , Anexinas/metabolismo , Antimetabólitos , Benzofenonas/síntese química , Bromodesoxiuridina , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Membrana Celular/fisiologia , Membrana Celular/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Corantes , Ensaio Cometa , Fragmentação do DNA/efeitos dos fármacos , Células HL-60 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Moleculares , Polimerização , Sais de Tetrazólio , TiazóisRESUMO
Here we present the preparation of a variety of diarylmethanes obtained via ultrasound Stille coupling under palladium catalysis between some substituted aryl compounds and benzyltributyltin compounds generated through sonicated Barbier reaction in a very short time reaction and excellent yield. The study reported below compares different methods to optimize the synthesis of usually unstable benzyltin derivatives and is another contribution to the investigation of Csp(3)-Csp(2) coupling process involving benzyl-aryl reagents. Substituted carboxylated benzophenones were easily prepared in a very good yield by oxidation of some diarylmethanes.
Assuntos
Antibacterianos/química , Antibacterianos/síntese química , Benzofenonas/química , Benzofenonas/síntese química , Metano/química , Metano/síntese química , Ultrassom , Técnicas de Química SintéticaRESUMO
Six derivatives of guttiferone-A (LFQM-79, 80, 81, 82, 113 and 114) were synthesized and evaluated for their antimicrobial activity against the opportunistic or pathogenic fungi Candida albicans (ATCC 09548), Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 69548), Candida tropicalis (ATCC 750), Cryptococcus neoformans (ATCC 90012), Trichophyton tonsurans, Microsporum gypseum and also against the opportunistic and pathogenic Gram-positive bacteria Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), Bacillus cereus (ATCC 11778) and Gram-negative Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 9027), Salmonella typhimurium (ATCC 14028), Proteus mirabilis (ATCC 25933). The antimicrobial activities of derivatives were compared with guttiferone-A and they presented to be more potent than the original molecule and sometimes greater than standard drugs established in therapeutics. The current study showed that derivatives of guttiferone-A possess potent antimicrobial activity and are relatively non-cytotoxic, which reveal these new molecules as promising new drug prototype candidates, with innovative structural pattern.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Benzofenonas/farmacologia , Fungos/efeitos dos fármacos , Antibacterianos/química , Antifúngicos/química , Bactérias/crescimento & desenvolvimento , Benzofenonas/síntese química , Benzofenonas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fungos/crescimento & desenvolvimento , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Less toxic drugs are needed to combat the human parasite Trypanosoma cruzi (Chagas's disease). One novel target for antitrypanosomal drug design is farnesyltransferase. Several farnesyltransferase inhibitors based on the benzophenone scaffold were assayed in vitro and in vivo with the parasite. The common structural feature of all inhibitors is an amino function which can be protonated. Best in vitro activity (LC50 values 1 and 10 nM, respectively) was recorded for the R-phenylalanine derivative 4a and for the N-propylpiperazinyl derivative 2f. These inhibitors showed no cytotoxicity to cells. When tested in vivo, the survival rates of infected animals receiving the inhibitors at 7 mg/kg body weight/day were 80 and 60% at day 115 postinfection, respectively.