ABSTRACT
To design and synthesize a series of novel scutellarein 4'-L-amino acid prodrugs with more potent anti-oxidative activity and improved physicochemical properties. Scutellarein was used as lead compound, according to successful experience of improving bioavailability of oral administration drugs by active transport mechanism, principle of hybridization was used to introducing L-amino acid structural fragments at 4'-position of scutellarein to design and synthesize target scutellarein 4'-L-amino acid prodrugs. The synthetic compounds were tested on their physicochemical properties and in vitro anti-oxidative activity against H202 induced oxidative damage in PC12 cells. Five compounds were found to have more potent anti-oxidative activity than positive control VE. Moreover the physicochemical properties of synthesized compounds were evaluated, and the results revealed that L-amino acid ether derivatives are more stable (t1/2 9-92 h) than their corresponding ester derivatives (t1/2 0.5 h). Water solubility of scutellarein 4'-L-amino acid ester and ether derivatives were 1 796-4 100 microg.mL-1 and 27.7-81.1 microg.mL-1 respectively, in comparison with scutellarin, the solubility of compounds 18, 19 and 22, 24-27 increased about 120-280 fold and 2-6 fold respectively. All these results suggested that L-amino acid prodrug strategy has significant potential in scutellarein prodrug design.
Subject(s)
Animals , Rats , Amino Acids , Chemistry , Antioxidants , Chemistry , Pharmacokinetics , Pharmacology , Apigenin , Chemistry , Pharmacokinetics , Pharmacology , Biological Availability , Drug Design , L-Lactate Dehydrogenase , Metabolism , PC12 Cells , Prodrugs , Chemistry , Pharmacokinetics , PharmacologyABSTRACT
A series of adefovir mono-L-amino acid esters, mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs with more potent anti-HBV activity and lower nephrotoxicity were designed and synthesized. Adefovir bis (L-amino acid) ester was used as lead compound, according to pathological and pharmacological findings that non-steroidal anti-inflammatory drugs can effectively inhibit the organic anion transporter 1 (hOAT1)-mediated adefovir phosphonic acid pairs of anion transport across tubular basement membrane thereby reducing the nephrotoxicity of adefovir. Flatten design principle was used to introducing non-steroidal anti-inflammatory drugs structural fragments to design and synthesize target adefovir mixture ester prodrugs. HepG2 2.2.15 cell line was used as in vitro anti-HBV activity evaluation model. Five compounds exhibited antiviral activity, and compound 18 showed the most potent anti-HBV activity and relatively high selective index (EC50 3.92 micromol L(-1), SI 9.97). HK-2 cell line was used as in vitro model to evaluate nephrotoxicity. Results suggested the target compounds have lower cytotoxicity than the positive control. Moreover, by analyzing the primary structure and activity relationship of these compounds, it could suggest that mono-L-amino acid ester, mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.
Subject(s)
Humans , Adenine , Chemistry , Pharmacology , Amino Acids , Chemistry , Pharmacology , Anti-Inflammatory Agents, Non-Steroidal , Chemistry , Pharmacology , Antiviral Agents , Chemistry , Pharmacology , Carboxylic Acids , Chemistry , Pharmacology , Cell Survival , Drug Design , Hep G2 Cells , Kidney Tubules, Proximal , Cell Biology , Metabolism , L-Lactate Dehydrogenase , Metabolism , Molecular Structure , Organophosphonates , Chemistry , Pharmacology , Prodrugs , Chemistry , PharmacologyABSTRACT
To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro (EC50 0.0952 micromol x L(-1), SI 69523). Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.
Subject(s)
Humans , Amino Acids , Chemistry , Antiviral Agents , Pharmacology , Cell Line, Tumor , Hepatitis B virus , Liver Neoplasms , Pathology , Virology , Nucleosides , Pharmacology , Organophosphonates , Pharmacology , Prodrugs , PharmacologyABSTRACT
According to the results of activity-structure relationship (SAR) studies of alpha1-adrenoceptor antagonists hydantoin-phenylpiperazine and benzimidazo-arypiperazine derivatves, to design and synthesize a series of novel phenylpiperazine alpha1-adrenoceptor antagonists with more potent vasorelaxant activity, active metabolites of naftopidil were used as lead compounds. Ten novel R,S-1-substituted phenyl-4-[3-(naphthal-yl-oxy)-2-hydroxy propyl]-piperazine were designed and synthesized, their vasorelaxant activity was evaluated by calculating inhibition rate of phenylephrine-induced vasocontration of rabbit artery trips. Five compounds exhibited vasorelaxant activity, and compound 16 showed significant vasorelaxant activity in vitro. At 0.01 and 1 micromol x L(-1), its inhibition rates were 7.03% and 22.72%, respectively. This compound possessed ideal vasorelaxant activity in vitro, and would be selected for further anti-hypertension evaluation in vivo. Moreover, by analyzing the primary activity and structure relationship of these compounds, it could be concluded that the SAR results of the reported phenylpiperazine alpha1-adrenoceptor antagonists could be used for reference in designing novel derivatives of naftopidil with optimal pharmacological properties.