Study On The Screening、preparation And Biological Activity Of Pleuromutilins Derivatives

At present, the incidence of tuberculosis has been high, primarily in the developing countries, because of various factors in developing,the control is faced with a series of challenges; the TB treatment period of treatment recommended by the world health organization is too long, for sensitive bacteria and drug-resistant bacteria infection, respectively, 20 months, 6 months of continuous treatment;The existing first-line anti-TB chemotherapy drugs was developed forty years ago, variety is limited, selectivity is very small; Moreover, prevalence of multi-drug-resistant tuberculosis(MDR-TB) and extensively drug-resistant tuberculosis(XDR-TB) is seriously hampering the progress of TB controlled. Severe controlled situation on Tuberculosis need new drugs of anti-TB, therefore, there is no time to think of developing a compounds imminent with new antibacterial mechanisms, better bioavailability and less cross-resistance to traditional antibiotics.In 1957, Italian Li Peiti company obtained rifamycin mixture separated from the mediterranean hammer fungal culture medium. rifamycin SV transformed from Rifamycin B was a highly efficient main anti-Gram-positive bacteria and Mycobacterium tuberculosis antibiotics, however, due to oral absorption of rifamycin SV, while antibacterial activity against gram-negative bacteria was not ideal, Therefore it conducted a study of semi-synthetic. In recent years, it has developed a series of new rifamycin derivative with not only strong antibacterial activity, but also broad spectrum antimicrobial, and extended half-life. WHO believes that the cost of new drugs Lifestyle hormone treatment of tuberculosis is low, received susceptible by patients. Therefore, since the research work on rifamycin derivative, the instruments and derivatives in synthetic effects are evolving, the resistance of infections is developing along the long-lasting, efficient, broad-spectrum, anti-drug and other direction.As a tricyclic diterpene antibiotic, valnemulin(pleuromutilin) acts mainly on the 50 S ribosomal subunit, makes the synthesis of bacterial protein blocked, and inhibits the peptidyl transferase activity, owning unique antibacterial activity, and it is hard produced cross-resistance and other characteristics, with traditional antibiotics used in clinical cross-resistance characteristics. Therefore, such derivatives is becoming the new study’s main focus for human use of antibiotics, such antibiotics as veterinary antibiotics have been widely used, The main representative of drugs are tiamulin(tiamulin) and valnemulin(valnemulin), In particular, in April 2007, the first pleuromutilins derivatives with antibiotics successfully listed on the approval of the Swiss him moline(retapamulin) by the U.S. food and drug administration(FDA), it achieved a leap from veterinary antibiotics to people with antibiotics, launched a new class of antibiotics for human use magic forest research and development of wave.Heterozygous drugs, which connect two different mechanisms of action of drugs via a covalent bond to form a stable, can have the dual role of the drug. The past ten years, researchers had begun to carry out a lot of their research work. The research on heterozygous drugs were very complex, with the unremitting efforts of scientists, hybrid drug research and development work has made significant progress, the world has developed a lot of these drugs and entered the stage of clinical trials.In this paper, hybrid drugs CBR-2092 developed by the cumber has entered phase Ⅱ clinical trial, which is the lead compound, mkes rifamycin antibiotics miao lin antibiotics new compound, rifamycin compounds screened is wonderful forest structure,which has a certain activity through the computer simulation. To rifamycin S-Na salt and derivatives of pleuromutili, hydrochloric acid valnemuli as starting material, by acidification, cyclization, hydrolysis, neutralization and condensation steps, synthesized rifamycin_valnemulin heterozygous.The synthesis process was simple to operate, low pollution, low cost, mild reaction conditions, the raw material was easy to obtain higher yield. Compounds was conformed by NMR(1H-NMR), nuclear magnetic resonance(13C-NMR), mass spectrometry(MS), infrared spectroscopy(IR) method. The results of biological activity test show good anti-TB bactericidal activity.This process follows design principles that the process was simple, the raw materials was easy to get, reaction conditions was mild, while the design process route route was verificated, in oder to obtain the target compound while exploring the optimum conditions. studies show that moisture content in the course of the cyclization influence hardly in the reaction system, Therefore acid used in the acidification process must be concentrated sulfuric acid or acetic acid; the basic strength of the catalyst in the reaction system during the hydrolysis has a big influence on the reaction conversion rate and product purity. The reaction temperature maintained at 60 ℃ was more appropriate, conversion of this step at the temperature can be up to 95%; Finally, the reaction of condensation and reduction achieve througth one pot method, the reaction need nitrogen protection, reaction temperature is room temperature, the choice of the reaction solvent has strong influence for the reactions, the reducing agent in the reduction process is highly selective sodium borohydride in acetic acid, The reaction temperature is room temperature.The target compound can be obtained in this process, Its purity can be upto 95% detected by HPLC, which Provides a reliable theoretical basis and has some practical value for the production process and operations further design optimization.