Synthesis And Antibacterial Mechanism Of Anti-Tuberculosis Cinnamaldehyde Derivatives And Metformin Derivatives

Tuberculosis(TB)is a chronic respiratory infectious disease caused by Mycobacterium tuberculosis(MTB).Tuberculosis remains to be one of the top ten fatal diseases in the world,which has been the leading cause of death from a single infectious disease since 2007.Mycobacterium tuberculosis can invade various organs throughout the body,but pulmonary is most common.In recent years,multidrug-resistant tuberculosis(MDR-TB)and extensively drug-resistant tuberculosis(XDR-TB)have emerged due to unreasonable treatment regimens,abuse of antibiotics,and incomplete treatment of tuberculosis.With the growth of population and the increase of population mobility,drug-resistant tuberculosis has become more and more serious,which gradually becomes a global public health crisis.There are now drugs for the treatment of tuberculosis.However,those drugs are easy to induce the emergence of drug-resistant bacteria because of the long treatment period.What's worse,most anti-tuberculosis drugs show liver toxicity.Therefore,the discovery of new drugs which can shorten the treatment period of tuberculosis is research focus in recent years.Cinnamaldehyde is an aldehyde natural organic compound with low polarity,poor water solubility,and low oral bioavailability.It shows pharmacological activities such as antibacteria,antitumor,reducing blood sugar level,lowering blood pressure,antioxidation,etc.,and it has been confirmed that cinnamaldehyde had an inhibitory effect on Mycobacterium tuberculosis.Guanidine compounds are a class of organic substances with strong alkalinity,which are in a completely proton state in the general physiological environment.Many natural products contain guanidyl functional groups,which have biological activities such as reducing blood sugar,lowering blood pressure,antivirus,antitumor and antibacteria.Metformin shows inhibitory effects onMycobacterium tuberculosis in diabetic patients with tuberculosis.However,the polarity of metformin is high.Besides,its bioavailability is low,and the antibacterial efficacy is poor.In order to improve the bioavailability of cinnamaldehyde and metformin and develop effective new anti-tuberculosis drugs.In this paper,according to the principle of skeleton splicing in drug design,based on the Schiff base reaction,nine compounds were synthesized using cinnamaldehyde and metformin as reaction materials.The nine synthesized compounds were screened for anti-mycobacterium tuberculosis activity.Except for the compound W05 synthesized by salicylaldehyde and thiosemicarbazone,which did not show inhibitory activity against Mycobacterium tuberculosis,the other compounds all had certain inhibitory effects on Mycobacterium tuberculosis,of which the compound W01 synthesized by isoniazid and cinnamaldehyde showed the highest activity.From these 9 compounds,the compound W01 with the highest anti-tuberculosis activity was selected.Molecular docking of W01 was performed by using Discovery Studio software,and Cyclopropane mycolic acid synthase(CmaA2)was screened as a possible target for compound W01.In summary,cinnamaldehyde and metformin were modified respectively,and 9compounds were synthesized successfully in this study.The antibacterial activity of these nine compounds against M.tuberculosis was evaluated.The target of the most potent compound W01 was preliminarily explored by using computer-assisted technology.The research has provided a new idea for the development of anti-tuberculosis drugs.