Design, Synthesis And Antibacterial Activity Study Of Thiapyran And Indole Derivatives

The discovery of antibiotics is considered to be one of the most important breakthroughs in modern medicine. However, the gradually increasing of bacterial resistance makes most of antibiotics lost their potency. With the wide spread use of antibiotics, some strains of Gram-positive bacterias such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and some Gram-negative bacterias such as vancomycin-resistant cocci (VRE), Pseudomonas aeruginosa and Acinetobacter baumannii began to show multidrug resistance (MDR), which cause much difficulty on clinical treatment. Therefore, the research and discovery of new antibiotics to treat bacteria resistance are imperative.Chuangxinmy was first discoveried by our institute, it was the first antibiotic found in China. Chuangxinmycin showed low toxicity and had no cross-resistance with antibiotics used in clinic. However, chuangxinmycin only exhibited moderate antibacterial spectrum, and it cann’t be given by injection, which affected chuangxinmycin’s widely use in clinic. As so far, among all the natural active products, only chuangxinmycin contains thiopyranoindole skeleton, the structure-activity relationship of chuangxinmycin need to be fulfilled.In this thesis, the structural skeleton was modified to get better understanding of structure-activity relationship of chuangxinmycin. Some prodrugs and derivatives of chuangxinycin were synthesized to improve their bioavailability.64 compounds (55 compounds are novel) were synthesized through 17 different synthetic routes from A to O, among which 37 compounds (32 compounds are novel) were target cmpounds. The structures of all target compounds were confirmed by both H-NMR and MS spectrum. Except compounds 5 and 22, all synthesized compounds showed no antibacterial activities. The antibacterial activity of compound 5 (MIC:2-4μg/ml) against MRSE, MSSE and MRSA was similar to chuangxinmycin (MIC:2-8μg/ml), lower than our pervious synthesized compound CV2 (MIC:0.06-0.12μg/ml). Compound 22 exhibited medium antibacterial activity with MIC values of 32μg/ml. The structure-activity relationship showed that:(1) The replacement of bromine, sulfonic acid and sulfonamide instead of hydrogen in C2 position of chuangxinmycin lead to lose of antibacterial activity; (2) The replacement of bromine and acetyl instead of hydrogen in C5 position of chuangxinmycin lead to lose of antibacterial activity; (3) The reduction and modification of carboxyl in C4 position of chuangxinmycin lead to lose of antibacterial activity; (4) The substitute of methyl in NH position of chuangxinmycin lead to lose of antimicrobial activity, however, when the substituent group is formyl, the antibacterial activity was retained; (5) The desulfurization compounds related to chuangxinmycin showed no antibacterial activity; (6) In the prodrug modification of chuangxinmycin, methyl-linker between two carbonyl groups lead to retain or enhance of the antibacterial activity, however, ethyl-linker or propyl-linker lead to loss of antimicrobial activity.In this thesis,64 chuangxinmycin derivatives were synthesized, their antibacterial activities were evaluated. Among them, compound 5 showed similar antibacterial activity to lead compound chuangxinmycin. The results of this thesis gave a foundation for future study.