Dihydrotriazin And Pyrimidin Guanidine Derivatives As Anti-bacterial Agents; Ursolic Acid Derivatives As PTP1B Inhibitory. Design, Synthesis And Biological Evaluation

Part ?:Design,synthesis and biological evaluation of dihydrotriazine and pyrimidin guanidine derivatives as antibacterial agentsBacterial infection is very common in people's life.In 2013,the Centers for Disease Control and Prevention reported that more than 11000 people died from MRSA-related infections in the United States alone.Therefore,it is an ongoing demand for new antibacterial agents.In this article,dihydrotriazin and pyrimidin guanidine derivatives were designed,synthesized and evaluated in terms of their antibacterial activities and cytotoxicity,respectively.The molecular docking test about the synthesized compounds was carried on.Most of the synthesized compounds showed potent inhibitory activities against the different bacteria,which obviously better than the positive control drug.In this part,76 compounds were designed and synthesized as summarized below.(1)Three novel series of dihydrotriazin derivatives containing a 6-benzyloxynaphthalen or(benzyloxy)benzylidene moiety were designed,synthesized and evaluated in terms of their antibacterial activities.Compounds 7a and 7c exhibited the highest activity of all the compounds synthesized against Staphylococcus aureus 4220 with an MIC value of 1 ?g/mL.Especially,compound 7a was the most potent,with an MIC of 1 ?g/mL against four multidrug-resistant,making it more potent than gatifloxacin and norfloxacin(MICs of 8 and 4 ?g/mL against MRSA 3167 and 3506,respectively).The cytotoxicity of compound 7a,7c and 7f were used a standard technique.Compound 7f exhibited weaker activity than 7c against the different bacteria,in spite of its slight greater cytotoxicity than 7c,comparably indicating that the promising antibacterial activity of these compounds may not be due to their cytotoxicity.To rationalize the observed antibacterial activity and understand the possible mechanism of action of these compounds,a docking investigation was undertaken.The preliminary docking results imply that compounds 7a and 7f possibly display their antibacterial activity through the interaction with DHFR protein by targeting residues of the active-site of DHFR.(2)Three novel series of 1,3-diaryl pyrazole derivatives bearing dihydrotriazin moieties were designed,synthesized and evaluated for their antimicrobial activities.The results revealed that most of the tested compounds exhibited good inhibitory potency against tested strains,among which compound 25c exhibited most potency with an MIC value of 1 ?g/mL against eight bacteria including drug-resistance bacteria MRSA and QRSA.The results of in vitro cytotoxicity showed that the tested compounds 25a,25b and 27n did not exhibit any remarkable cytotoxicity.To rationalize the observed antibacterial activity and understand the possible mechanism of action of these compounds,a docking investigation was undertaken.The preliminary docking results imply that compounds 25a,25b and 271 possibly display their antibacterial activity through the interaction with DHFR protein by targeting residues of the active-site of DHFR.(3)A total of 22 of pyrimidin guanidine derivatives were designed,synthesized and evaluated in terms of their antibacterial activities.The results revealed that most of the tested target compounds exhibited good inhibitory potency against tested strains.Among which,compound 34c presented the most potent activity,representing a four-fold increase in the potency relative to the standard drug norfloxacin(MIC = 8 ?g/mL and 4 ?g/mL)and a 64-fold increase relative to oxacillin(MIC>64 ?g/mL)against MRS A 3506 and 3167 strains with an MIC value of 1 ?g/mL,and further bioassays are in progress.Part?:Design,synthesis and biological evaluation of ursolic acid derivatives as inhibitors of PTP1BProtein tyrosine phosphatases 1B(PTP1B)acts as a key negative regulator in both insulin and leptin signaling pathways,thereby modulates both glucose and lipid metabolism.Thus,small molecule PTP 1B inhibitors have considerable therapeutic potential for the treatment of Type 2 diabetes and obesity.During the last decade,various PTP 1B inhibitors have been developed and reported,compounds with a pentacyclic triterpene core have been studied for PTP 1B inhibitors,and especially triterpenoids derived from ursolic acid(UA)exhibit potential PTP IB inhibitory activity.However,a major inconvenience for these pentacyclic triterpenoids is their poor water solubility and selectivity against PTPs.Hence,it is still the focus to develop small molecule PTP 1B inhibitors with good selectivity.In this article,three series of ursolic acid derivatives were designed and synthesized,PTP 1B inhibitory activity study and in vitro cytotoxicity evaluation were carried on.The results showed that most of the tested compounds showed potent PTP 1B inhibitory activity.In this part,21 compounds were designed and synthesized as summarized below.(4)Three series a total of 21 of ursolic acid derivatives were designed,synthesized and evaluated for PTP 1B inhibitory activity.Results revealed that most of the compounds exhibited potent PTP1B inhibitory activity.Among which,compound 11e showed an IC50 of 4.15 ?M against PTP 1B.The results of the cytotoxic tests indicated that these series of compounds did not exhibit any remarkable cytotoxicity.To rationalize the observed PTP 1B inhibitory activity and understand the possible mechanism of action of these compounds,a docking investigation was undertaken.The preliminary docking results imply that compound 11e display its inhibitory activity through the interaction with PTP1B protein by targeting residues of the active-site of PTP1B,and further bioassays are in progress.Conclusions:In summary,97 compounds were designed and synthesized,the structure-activity relationships were also discussed.The structure of target compounds were confirmed by MS,1H-NMR,13C-NMR and HRMS.The work might provide an experimental basis for the development of new candidates with potent antibacterial activities and PTP1B inhibitory activities for the clinical treatment,respectively.