E-mail addresses:ying.(Y.Wang),(J.-G.Wang).

The invention of antibiotics was regarded as one of the greatest medicinal improvements in the 20th century,because thousands of patients had been rescued from fatal bacterial ,with the abuse of antibiotics,resistance against these drugs to bacteria has become a global problem 2008,Rice termd “the ESKAPE bugs”to describe Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumonia,Acinetobacter baumanni,Pseudomonas aeruginosa and Enterobacter as the most common resistant bacteria species in hospitals[1].In 2010,a carbapenemase named New Delhi metallo-beta-lactamase-1(NDM-1),was reported to cause Gram-negative bacterial resistance to almost all availableβ-lactam antibiotics and the rapid spread of the plasmid-encoded NDM-1 gene in some countries subsequently indicated that“superbug”era was arriving[2,3].

NDM-1 belongs to the class B metallo-β-lactamase(MBL)superfamily,which contains enzymes that hydrolyzeβ-lactams and cleaves the β-lactam ring of the compound,leading to antibiotic-resistant infections[4].Crystal structures of NDM-1 had been elucidated by different research groups,either the free enzyme alone or thatin a bound form[4-8].wo catalytic zinc ions have been found in the active site of the enzyme,which play essential roles for the biochemical function of this NDM-1 crystal structures were bound either with the hydrolyzed state of an antibiotic drug,or an inhibitor such as achievements have not only provided structural insights intoβ-lactam recognition and inhibition mechanism,but also offered opportunities to design novel inhibitors targeting NDM-1 in a rational way[7,8].

Very few medicinal antibiotics can inhibit resistant bacteria with NDM-1 gene effectively,including colistin and 2000 to 2013 only 22 new antibiotics were approved,but none of them was indicated for Gram-negative bacteria[9].It is therefore a strong demand to develop novelinhibitors tackle such a bacterial that captopril is an NDM-1 inhibitor with IC50of 7.9μmol/L[4],based on which some captopril analogues were synthesized and evaluated[10].Proschaket some approved drugs containing thiols and identified some good NDM-1 inhibitors[6].Aspergillomarasmine A(AMA)was shown to be a rapid and potent NDM-1 inhibitor,the IC50of which is 4.0μmol/L[11].Ebselen was reported to be a potent covalent inhibitor of NDM-1,which binds to Cys211 to inactivate the enzyme[12].Chenget some active compounds via multistep virtual screening and the most potent inhibitor VNI-41 has an IC50of 29.6μmol/L[13].Yang1IF]et that triazolylthioacetamide is a promising scaffold for the development of NDM-1inhibitors,and the best IC50value is 0.15μmol/L for compound 4a in their study[14].

Isatin is an endogenous natural product and its derivatives possess a wide range of biological activities,such as antibacterial,antitubercular,antimalarial,antifungal and antiviral activities[15-20].Some drugs contain isatin as an active scaffold,for instance,indirubin and methisazone,which have been used to treat chronic myelogenous leukemia and smallpox infection,respectively[21,22].It is a common knowledge that the most fruitful basis for the discovery of a new drug is to start with an old drug[6,23].In the course of screening new chemical agents for resistant bacteria,we had evaluated the inhibitory activity of some medicines containing isatin structure against purified was found to display some activity in the screening process,although the IC50value for NDM-1 of this old drug is only 297.6μmol/ by this result,we then synthesized some isatin-β-thiosemicarbazone (IBT)derivatives designed from methisazone and tested their in vitro inhibitory biological potencies were observed for the IBT compounds and many IC50values against NDM-1 are at micromolar we have identified for the first time that a series of IBT compounds are new NDM-1 inhibitors,which is meaningful for further drug illustrated the chemical structures of some reported NDM-1 inhibitors,isatin,indirubin and methisazone.

The synthetic method for the IBT compounds was similar to our previous procedure,in which the target compounds were chemically prepared by a straightforward condensation of isatin and thiosemicarbazide[24].The yields of the reaction were generally satisfactory,in the range of 65%～80%.For examples,the yield of compound 6 is 58%while that of compound 7 is 81%.The synthetic scheme,chemical structures of compounds 1-14 and their in vitro inhibitory activities against NDM-1 are shown in Table 1.The inhibitory potencies of the IBT derivatives are sorted in ascending 3,4,6,7 and 13 are new compounds that have not been characterized before,whereas the other compounds had been reported and detailed elsewhere[24-26].Detailed experimental procedures,analytical data for all previously unreported compounds,1H NMR,13C NMR and HRMS figures for selected compounds,relevant biological data and inhibition curves for all NDM-1 inhibitors are in Supporting information.

structures of reported NDM-1 inhibitors and some drugs containing isatin scaffold.

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