RESUMO
Due to the rising prevalence of Alzheimer's disease (AD), there is a pressing need for more effective drugs to treat or manage AD's symptoms. Studies have shown that cholinesterase inhibition can improve cognitive and behavioral symptoms associated with AD, by addressing the cholinergic deficit. Based on the recent development of cholinesterase inhibitors with indoloquinoline and triazole moiety, we rationalized that compounds with an isocryptolepine-triazole scaffold may also have the same biological targets. In this study, eighteen previously synthesized isocryptolepine-triazole compounds were assessed for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholine esterase (BChE). The majority of these compounds demonstrated potent selective AChE inhibition. Furthermore, our molecular docking and molecular dynamic simulation studies reveal that the isocryptolepine and triazole moieties are important for the binding of the compounds with the periphery of the AChE's binding pocket. While reductions in molecular weights and lipophilicities may be necessary to improve their pharmacokinetic properties, this work provides valuable insights for designing future AChE inhibitors, based on the novel isocryptolepine-triazole scaffold.
RESUMO
A series of aporphines conjugated with an N-benzylpyridinium moiety through an amide-bond linkage were synthesized and evaluated for their acetylcholinesterase (AChE) inhibitory activity. The conjugation of the N-benzylpyridinium group significantly enhanced the AChE inhibitory activity of the core aporphine. The halogen substituents on the benzyl group affected the activity of the conjugates. Both (S)- and (R)-enantiomers of three conjugates with low IC50 values were synthesized and evaluated for their activities. All (S)-enantiomers exhibited higher activity than the corresponding (R)-enantiomers. The (S)-enantiomer of 2-chlorobenzylpyridinium-containing aporphine was the most potent inhibitor in this study with an IC50 value of 0.06 ± 0.003 µM. Molecular dynamics simulation analysis revealed that both enantiomers can interact with the AChE binding site, whereas the (S)-enantiomer possessed slightly stronger interaction than the (R)-enantiomer, presumably because of their different orientations, as evidenced by molecular docking. The N-benzylpyridinium dehydroaporphine conjugates were also synthesized but were less active than the corresponding aporphine conjugates.
RESUMO
Eighteen hybrid compounds between 8-bromo-2-fluoro-isocryptolepine (4) and 1,2,3-triazole were synthesized via azide rearrangement-annulation reaction. Compound 4 underwent regioselective N-propargylation and click reaction to form 8-bromo-2-fluoro-isocryptolepine-triazole hybrids 11 which were evaluated for cytotoxic activity. Compound 11 c containing 1-anisyltriazole was the most effective in inhibiting HepG2, HuCCA-1 and A549 cell lines (IC50 values of 1.65-3.07â µM) while compounds 11 a (1-phenyltriazole), 11 j (1-para-CF3 -benzyltriazole) and 11 l (1-meta-Cl-benzyltriazole) were potent inhibitors of HuCCA-1, HepG2 and A549 cell lines, respectively. Moreover, 11 l showed the lowest cytotoxicity to normal human kidney cell line. Compounds 11 c and 11 l provided improvement of cytotoxic activity over 4. Compounds 4, 11 c and 11 l were selected to investigate their mechanisms of action. The results showed that 4 could induce G2/M cell cycle arrest and was involved in the upregulation of p53 and p21 proteins. However, the mechanisms of growth inhibition by 11 c and 11 l were associated with G0/G1 cell cycle arrest and mediated by induction of oxidative stress.
Assuntos
Antineoplásicos/farmacologia , Alcaloides Indólicos/farmacologia , Quinolinas/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Estrutura Molecular , Quinolinas/química , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
A series of 3-amino-6,7-dimethoxycoumarins conjugated with the N-benzylpyridinium moiety through an amide-bond linkage was synthesized and evaluated for their acetylcholinesterase inhibitory activity. A number of the benzylpyridinium derivatives exhibited potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3-difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 ± 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme.
RESUMO
Phytochemical constituents in alkaloid extracts from three Thai club mosses Huperzia squarrosa, Huperzia phlegmaria and Phlegmariurus nummularifolius were investigated. Squarrosinoxide was an undescribed Lycopodium alkaloid from H. squarrosa possessing an unprecedented 6/5/7 tricyclic spiro system. Acetyllycophlegmarianol was an undescribed N-oxide lycopodine-type alkaloid isolated from H. phlegmaria. 4-Epilycopodine, an undescribed epimer of lycopodine, was first isolated from P. nummularifolius. The structural assignments were established through comprehensive spectroscopic techniques and chemical correlations. All compounds were assayed for their anti-acetylcholinesterase activity in vitro.
Assuntos
Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Lycopodiaceae/química , Lycopodium/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Electrophorus , Conformação Molecular , TailândiaRESUMO
Essential oil of fresh leaves of Ocimum gratissimum (OGEO) was water-steam distilled and analyzed by GC-MS. Thirty-seven compounds were identified, with eugenol (55.6%) as the major component followed by cis-ocimene (13.9%), γ-muurolene (11.6%), (Z,E)-α-farnesene (5.6%), α-trans-bergamotene (4.1%), and ß-caryophyllene (2.7%). Antimicrobial activity of OGEO was tested against four gastroenteritis pathogens (Staphylococcus aureus, Escherichia coli, Salmonella Typhimurium, and Shigella flexneri). OGEO exhibited antibacterial effect, with MICs of 1-2â¯mgâ¯ml-1, against the tested species. OGEO also displayed rapid killing effect within 5â¯s at four times of MIC against both E. coli and S. Typhimurium. Various assays were performed to investigate the mode of action of the oil. OGEO increased the permeability of microbial cell membrane as evidenced by LIVE/DEAD BacLight assay. Analyses of the release of absorbing materials at 260â¯nm, protein leakage, SDS-PAGE, and SEM strongly suggested the disruptive action of the oil on the cytoplasmic membrane of the tested microorganisms. Results revealed that the antibacterial property of OGEO could be due to membrane disruption.
Assuntos
Antibacterianos/farmacologia , Gastroenterite/microbiologia , Ocimum/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Óleos de Plantas/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Eugenol/química , Cromatografia Gasosa-Espectrometria de Massas , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Óleos Voláteis/farmacologia , Pentanóis/química , Óleos de Plantas/química , Sesquiterpenos Policíclicos , Salmonella typhimurium/efeitos dos fármacos , Sesquiterpenos/química , Shigella flexneri/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
A series of scopoletin derivatives incorporated with the pyridinium moiety was synthesized and evaluated for their acetylcholinesterase (AChE) inhibitory activity by the colorimetric Ellman's method. A 2-fluorobenzylpyridinium derivative was the most potent among the tested compounds, with an IC50 value of 0.215±0.015µM, which was greatly improved from that of scopoletin. Docking studies revealed that the scopoletin portion of the mentioned compound was bound to the peripheral anionic site of the AChE, whereas the N-benzylpyridinium residue to the catalytic anionic site.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Escopoletina/análogos & derivados , Escopoletina/farmacologia , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Escopoletina/síntese química , Escopoletina/química , Relação Estrutura-AtividadeRESUMO
Coronarin D is a labdane-type diterpene from the rhizomes of Hedychium coronarium. In the view of our ongoing effort to explore its novel biological activity, antimicrobial activity study of coronarin D was performed. The results showed that coronarin D was active against tested Gram-positive bacteria, inactive for tested Gram-negative bacteria, and weakly active against tested fungi. The antibacterial effect of the combination of coronarin D with nine classical antibiotics against four Gram-positive bacteria was also evaluated. The fractional inhibitory concentration indices (FICI) of coronarin D-antibiotics combinations, calculated from the checkerboard assay, were used as synergism indicator. Out of 36 combinations, 47% showed total synergism, 33% had partial synergistic interaction, 17% showed no effect, and 3% showed antagonism. By combination with coronarin D at concentration of 0.25 minimal inhibitory concentration (MIC), the activities of antibiotics were boosted to 4- to 128-fold. These finding suggested an attractive approach to combat the infectious diseases by using coronarin D-antibiotic drug combination.
Assuntos
Diterpenos/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/administração & dosagem , Anti-Infecciosos/administração & dosagem , Sinergismo Farmacológico , Fungos/efeitos dos fármacos , Humanos , Testes de Sensibilidade MicrobianaRESUMO
A new prenylated isoflavone, pomiferin-4'-O-methyl ether, and a new prenylated chalcone, 2',4'-dihydroxy-4-methoxy-3'-(2-hydroxy-3-methylbut-3-enyl)chalcone, together with four known flavonoids, were isolated from the leaves of Derris malaccensis. All isolated compounds were evaluated for their cytotoxicity.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Derris/química , Folhas de Planta/química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Flavonoides/química , HumanosRESUMO
The cytotoxic activity of five alkaloids, namely 4,5-dioxo-dehydrocrebanine (1), dehydrocrebanine (2), crebanine (3), oxostephanine (4), and thailandine (5) isolated from the tuber and leaves of Stephania venosa (Blume) Spreng was investigated. Thailandine showed the strongest activity against lung carcinoma cells (A549) (IC50 of 0.30 µg/mL) with very low cytotoxicity against normal embryonic lung cells (MRC-5). Thailandine also demonstrated strong activity against Plasmodium falciparum, K1 strain (IC50 of 20 ng/mL), and Mycobacterium tuberculosis H(37)Ra (MIC of 6.25 µg/mL) as well as gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus. Oxostephanine exhibited strong activity against breast cancer (BC) and acute lymphoblastic leukemia cells (MOLT-3) with an IC50 of 0.24 and 0.71 µg/mL, respectively, and exhibited very low cytotoxicity against MRC-5 cells. Dehydrocrebanine demonstrated strong activity against promyelocytic leukemia cells (HL-60) with an IC50 of 2.14 µg/mL whereas crebanine showed weak activity against cancer cell lines. However, both of them showed cytotoxicity against MRC-5 cells.
Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Aporfinas/farmacologia , Extratos Vegetais/farmacologia , Stephania/química , Alcaloides/química , Alcaloides/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Aporfinas/química , Aporfinas/isolamento & purificação , Aspergillus fumigatus/efeitos dos fármacos , Candida/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Bactérias Gram-Positivas/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Phialophora/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Tubérculos/química , Plasmodium falciparum/efeitos dos fármacos , TailândiaRESUMO
In the title mol-ecule, C(17)H(10)BrNO(3), the mean planes of tricycle and bromo-phenyl fragments form a dihedral angle of 75.5â (1)°. In the crystal, π-π inter-actions [centroid-centroid distances = 3.556â (2) and 3.898â (8)â Å] between the isoquinoline systems link mol-ecules into stacks parallel to the a axis. The crystal packing also exibits weak inter-molecular C-Hâ¯O hydrogen bonds.
RESUMO
Ten dipyridodiazepinone derivatives were synthesized and evaluated for their anti HIV-1 reverse transcriptase activity against wild-type and mutant type enzymes, K103N and Y181C. Two of them were found to be promising inhibitors for HIV-1 RT.
RESUMO
A new labdane diterpenoid, (E)-labda-8(17),12-dien-15,16-olide (1) together with eight known compounds, coronarin D (2), coronarin D methyl ether (3), coronarin D ethyl ether (4), isocoronarin D (5), coronarin B (6), labda-8(17),11,13-trien-15,16-olide (7), (E)-labda-8(17),12-diene-15,16-dial (8) and 16-hydroxylabda-8(17),11,13-trien-15,16-olide (9), are isolated from the rhizomes of Hedychium coronarium. Compounds 2-4, 5 and 9 are isolated as mixtures of C-15, C-14 and C-16 epimers, respectively. Their structures are determined on the basis of their spectroscopic data. The epimeric mixtures of 2 and 3 have not been reported before. Some of them were evaluated for their cytotoxicity.
Assuntos
Diterpenos/isolamento & purificação , Zingiberaceae/química , Cromatografia em Camada Fina , Diterpenos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Based on the molecular modeling analysis against Y181C HIV-1 RT, dipyridodiazepinone derivatives containing an unsubstituted lactam nitrogen and 2-chloro-8-arylthiomethyl were synthesized via an efficient route. Some of them were evaluated for their antiviral activity against HIV-1 RT subtype E and were found to exhibit virustatic activity comparable to some clinically used therapeutic agents.