The Design And Synthesis Of Novel Rhodanines As Antibacterial Agents

Based on the "combination principles", which was widely used in design strategy of new drugs,221 fused heterocyclic compounds were obtained by the combination of the rhodanines with a chalcone, chalcone isostere 2-phenoxy-1-acetophenone or N-phenyl-substituted pyrazole. The structures of the desired compounds were characterized by 1H-NMR, mass spectra. Part of the compounds was also characterized by 13C-NMR. All the compounds synthesized were evaluated for their antimicrobial activity. And a cytotoxicity evaluation was also conducted on the compounds with better potency. The objective of this paper was to find a candidate drug to pave the way to the further research.The research of this dissertation could be divided into three chapters as follows:(1) Four series of rhodanines bearing chalcone moiety were designed, synthesized and evaluated for their antibacterial activity in vitro. Results revealed that most of the compounds exhibited good inhibitory activities with MICs in a range of 2-16μg/mL. Among which, compounds 14g presented the most potent activity, representing a four-fold increase in the potency relative to the standard drug norfloxacin (MIC=8 μg/mL and 4μg/mL) and a 64-fold increase relative to oxacillin (MIC> 64μg/mL) against MRSA CCARM 3167 and 3506 strains with an MIC value of 1μg/mL, and a 32-fold increase relative to norfloxacin (MIC> 64μg/mL) but slightly less active than oxacillin (MIC=1μg/mL) against the QRSA CCARM 3505 and 3519 strains.(2) Five series of rhodanines bearing 2-phenoxy-1-acetophenone moiety were designed, synthesized and evaluated for their in vitro antibacterial activity. Results revealed that two series of the compounds (20 and 22) exhibited good inhibitory potency with MIC values in range of 2-8μg/mL. Among which, compounds 22c exhibited the strongest potency with an MIC value of 1μg/mL against seven S. aureus bacterias including drug-resistance bacterias MRSA and QRSA, which is comparable to norfloxacin but slightly weaker than oxacillin.(3) Twelve series rhodanines bearing N-phenyl-substituted pyrazole moiety were designed, synthesized and evaluated for in vitro antibacterial activity. Results revealed that several series of the compounds exhibited good inhibitory potency against five strains (S. aureus 4220, MRSA 3167 and 3506, QRSA 3505 and 3519). Among which. compound 36b,36g and 36m exhibit good potency (MIC=1μg/mL) against drug-resistance bacterias MRSA and QRSA, which is comparable to norfloxacin but slightly weaker than oxacillin. No compound exhibited any activity against the S. aurezis 209 and S. aurens 503 at 64μg/mL.The combination situation of rhodanines-based three types of active sub-structures was studied comprehensively. All the compounds synthesized were evaluated for their in vitro antibacterial activity against eight bacteria. Activity screening results showed that most of the compounds reached the expected activity. And some of the target compounds exhibited considerable potency of inhibiting the growth of some Gram-positive bacteria including resistant stains, which were more potent than norfloxacin but comparable to oxacillin. Regretfully, none of the compounds exhibited any activity against the E. coli 1356 at 64μg/mL.