Synthesis And Characterization Of Captopril Derivatives

In order to study structure-activity relationship of captopril, this study adoptcoupling method, and synthesize a series of captopril derivatives, including thiol sideand carboxy-terminal modification. Otherwise, we design and synthesize severalchitosan-captopril sustained release drug carrier systems, choosing chitosan as thecarrier and captopril as a model drug. The detailed content includes the followingsections:(1) Because of the captopril microspheres and microcapsules frequently showburst release phenomenon, and in the preparation process, toxic cross-linking agentsuch as formol or glutaraldehyde are usually used. This study choose chitosan aspolymer skeleton, adopt the coupling method and prepare captopril sustained releasesystem by covalent bond. We synthesized chitosan-captopril andchitosan-lysyl-captopril, the target product were charactered by IR, which prove thesuccessful synthesis of the target compound. This system aimed at overcoming burstrelease phenomenon, improving efficacy, reducing delivery times and adversereactions.The in vitro release experiment results show that two sustained-release drugcarrier system has a good release effect, the cumulative release rate ofchitosan-captopril in PBS (pH=7.4) and HCl-KCl buffer solution (pH=1.2) for 72 hare 59.2% and 78.36% respectively. The cumulative release rate ofchitosan-lysyl-captopril in PBS and HCl-KCl buffer solution for 72h are 55.2% and76.36% respectively. This is expected to become the ideal delivery system forwater-soluble drugs.(2) The thiol of captopril plays an important role in ACE inhibition. The captoprilderivatives may show higher activity and reduce the adverse reactions by esterifyingof thiol or replacing the thiol with carboxyl group. This study synthesized severalthiol-side modification of captopril derivatives, including acetylcaptopril,benzoylcaptopril, cinnamoyl-captopril, three captopril derivatives were characterized by IR and MS, which proved the successful synthesis of the target compounds.(3) This study synthesized several amino acid methyl ester hydrochloride byCH3OH-SOCl2, including glycine methyl ester hydrochloride, alanine methyl esterhydrochloride, aspartic acid dimethyl ester hydrochloride, lysine methyl esterhydrochloride. We modified the carboxy-terminal of captopril with amino acid methylester, and synthesized a series of captopril derivatives, including captopril- glycinemethyl ester, captopril-alanine methyl ester, captopril-aspartic acid dimethyl ester,captopril-lysine methyl ester, captopril-EDC. The results show that the reactioncarried under EDC/HOBt/DMAP or EDC/NHS/DMAP in dichloromethane showingthe best outcome, the desired product were characterized by IR and MS, which provedthe successful synthesis of the target compounds.This study aims to construct more reliable chemical feature basedpharmacophore models for ACE inhibitors. This model may serve as a guide inidentifying selective ACE inhibitors, and provide a certain reference value for thecaptopril modification.