Design, Synthesis And Biological Activity Studies Of Novel Anti-tubercular Drugs

Since the mid-1980s, the controlled infectious disease tuberculosis (TB) has beenundergoing resurging. The existing anti-TB treatment program is also far fromsatisfaction, since the resistance strains are still continually emerging, as well as theappearance of multi-drug resistant (MDR) strains of M. tuberculosis have highlighted.Therefore it's urgent to discover new targets for antituberculotics and develop novelantituberculotics. The shikimate pathway which leads to the biosynthesis of chorismicacid, is characteristic and essential to plants and microorganisms for the biosynthesisof aromatic compounds. The enzymes of this pathway are hence potential targets forthe development of specific antimicrobial agents. This study aimed at discoveringnovel tuberculostatics with no tolerance.Using virtual screening against small molecule bank, the lead compound SDI01were hited as M. tuberculosis shikimate dehydrogenase (SDH) inhibitor with MICvalue of 6μg/mL. In the principles of group replacement, bioisosterism andcombination, we designed and synthesized 32 derivatives of SDI01, and got somepreliminary structure-activity relationships after determining their anti-TB activities invitro. Compounds with small lipophilic group substituent at the C-4 position ofbenzene ring exhibited better activity. When the benzene ring was replaced byheteroaromatic ring, the compounds showed less antibacterial activity. Activity couldbe improved when ethylenediamine group was replaced by homopiperazine ring.Since these new highly potent SDH inhibitors act at new target and possess uniquechemical structures with existing antituberculotics, they are worthy to be furtherstudied and developed.Rifamycins are important agents in the treatment of infectious TB. By the reasonof the tolerance of existing rifamycins, it is important to develop new drugs withoutcross-resistance with currently used drugs. This study was also focused on exploringthe novel rifamycins by modifying the C3 side chain of the rifamycins. We designedand synthesized eight rifamycin derivatives. The preliminary in vitro results of thebiological evaluation demonstrated high antimycobacterial activity of thesecompounds. Derivatives such as DW-35, DW-36 and DW-37 had MICs 8 to 16 times lower than those of rifampicin against sensitive M. tuberculosis strains, and they alsoshowed higher biological activity against all three classes of mutants resistant torifampicin. MTT assay on human macrophages THP-1 cells, compound DW-35appeared no obvious cytotoxicity with the IC₅₀ value 543.12μg / mL in theconcentration range of 3.125-100μg / mL, and compound DW-37 had no significantcytotoxicity in the range of 3.125-12.5μg / mL with the IC₅₀ value 51.18μg / mL.Therefore, these derivatives have good prospects for further research anddevelopment.