Synthesis And Screening Of Antiviral Drugs For Influenza And Anti-osteoporosis Drugs

The paper contains two contents.1. The Synthesis and Screening of Anti-influenza Agents.In order to synthesize new sialic acid analogs and find new. ldnds of anti-influenza agents, we made some chemical modification on guanidine and carboxy in the structure of zanamivir and tested their anti-influenza activity. First, based on the isosteric theory, we synthesized some alkylcarbamido substituted Neu5Ac2en derivatives by replacing the guanidine of zanamivir with alkylcarbamido and evaluated their anti-influenza activity. Second, to obtain better oral activity, we synthesized a new series of analogs of zanamivr by esterification using three long -chain alkoxyalkanols. In order to investigation the effect on the anti-influeniza activity of carboxyl and based on the previous work, we also synthesized some guanidine substituted cyclopentane derivatives without carboxyl. In this part, three novel series total 47 compounds (31 unreported) were synthesized and verified by MS and NMR.The activities of 31 unreported compounds against influenza virus were evaluated on neuraminidase(NA) and in cell models, the results demonstrated that compound Cla, Clb and Clc have positive activities against influenza NA. To the four tested influenza'A strains, the IC₅0 of compound Cla ranged from 0.315 to 18.96μM, the IC₅0 of compound Clb ranged from 0.301 to 18.1μM, the IC₅0 of compound Clc ranged from 0.226 to 26.8μM, the IC₅0 of zanamivir ranged from 0.075 to16.75μM. The activities of compound Cla-b on influenza A/Jingfang/262/95 (H1N1) is almost as strong as that of zanamivir, the activities of compound Clc on influenza A/Hanfang/359/95(H3N2) is 1/15 of that of zanamivir. To the three tested influenza B strains, the IC₅0 of compound Cla ranged from 23.38 to＞37.88μM, the IC₅0 of compound Clb ranged from 22.30 to 23.45μM, the IC₅0 of compound Clc ranged from 21.87 to 247μM, the IC₅0 of zanamivir ranged from 223 to 5018μM. The activities of compound Cla-c on influenza B is stronger than that of zanamivir. The activities of compound Clb on influenza B/Jifang/13/97 is 314 times of that of zanamivir. The in vitro evaluation result showed that compounds Cla-c had activities on both influenza A and B, and the activities on influenza A is stronger than on influenza B compared to that of zanamivir.In vivo activities of compound Clc against influenza A(FM1) were evaluated in mice, intragastric administration of compound Clc 62.5 and 31.25mg/kg showed no difference on mice body weight. Oral administrated of compound Clc, three dose groups all showed statistics significant difference compared with that of vehicle group on survival and mean day to death. 62.5mg/kg group showed statistics significant difference compared with that of vehicle group on lung consolidation. 62.5 and 31.25mg/kg group showed statistics significant difference compared with that of vehicle on mean lung score.The LD₅0 of intragastric administration of compound Clc is about 1000mg/kg, the LD₅0 of peritoneal injection is more than 500mg/kg.So the pharmacology of compounds Cla-c needs more time to investigate, they had potential to be developed into clinical drugs.2. The Synthesis and Evaluation of Anti-osteoporosis Agents Acting on BMP-2 Promoter.Great progress was made in osteoporosis therapy, but drugs used in clinic are lack of specificity, and generally have some severe side effect. In order to get new type agents with stronger tissue specificity that can improve metabolic balance of osteoporosis, we found 2-acetyl-benzothiophen has visible activity in increasing BMP-2 level with the help of promoting BMP-2 level anti-osteoporosis screening model targeting on BMP-2 promoter, and found that 2-acetyl-benzothiophen had potential to be future developed for clinical drugs.Based on the previous research, five series of benzothiophene (benzofuran, indole, thiophene, furan) derivatives were synthesized in order to get new agents with specificity on osteoporosis. 20 unreported compounds among the 32 obtained compounds were synthesized and were verified by MS and NMR.The activities of promoting BMP-2 level of 32 compounds and 6 compounds bought from others were tested. The majority of them showed activity on BMP-2, and compound 1, 3, 27, 29, 37showed better activity than Lovastatin, compounds 5, 14, 23, 31 showed similar activities as that of Lovastatin. Others showed smaller activities than that of Lovastatin. The activities of compound 1 and 3 on BMP-2 is distinguished, their In vivo activities are evaluating now in ovariectomized mice.The activities of undersaturated benzoheterocycle or undersaturated heterocycle on BMP-2 is discovered and reported by our institute first, they had potential to be developed into primer of new structure type leading compound for anti-osteoporosis drug study.In this paper, totally 79 compounds were synthesized including 51 unreported, and all their structures were elucidated by NMR and MS.