Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates

A series of ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates, 8a-11v, were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The selective indexes of inhibition on replication of HBV DNA of compounds 11s (>8.7) and 11t (10.8), which were introduced halogen on the phenyl ring at position 2, were greater than those of the other evaluated compounds including lamivudine (7.0). Compounds 9e, 9h, 9l, and 11v exhibited significant anti-HBV activities, and the IC(50) values on replication of HBV DNA of these compounds were 3.6, 6.37, 5.2, and 5.4 microg/ml, respectively, which were far more potent than the positive control lamivudine 228 microg/ml.     

Synthesis and anti-hepatitis C virus activity of novel ethyl 1H-indole-3-carboxylates in vitro

A series of ethyl 1H-indole-3-carboxylates 9a_1–6 and 9b_1–2 were prepared and evaluated in Huh-7.5 cells. Most of the compounds exhibited anti-hepatitis C virus (HCV) activities at low concentration. The selectivity indices of inhibition on entry and replication of compounds 9a₂ (>10; >16.7) and 9b₁ (>6.25; >16.7) were higher than those of the other evaluated compounds, including the lead compound Arbidol (ARB, 6; 15). Moreover, the selective index of inhibition on entry of compound 9a₃ (>6.25) was higher than that of ARB (6). Of these three initial hits, compound 9a₂ was the most potent.     

Synthesis and anti-hepatitis B virus evaluation of novel ethyl 6-hydroxyquinoline-3-carboxylates in vitro

A series of non-nucleoside ethyl 6-hydroxyquinoline-3-carboxylate derivatives were prepared and evaluated in HepG2.2.15 cells. Most compounds inhibited the expression of viral antigens HBsAg or HBeAg at low concentration. Six compounds, 9f(3), 12b(6), 12f(6), 13b(2), 13b(6), and 13f(6), displayed excellent intracellular inhibitory activity and selectivity towards the replication of HBV DNA. Of these six initial hits, compound 13b(6) was the most active.     

Synthesis and in vitro insulin-mimetic activities of zinc(ii) complexes of ethyl 2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxylates

Several Zn(II) complexes (2a-e) of 1-arylmethyl-2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxylates (1a-e), known drug candidates for diabetic complications, were synthesized and proved to have in vitro insulin-mimetic activities, suggesting that these complexes are potential chemotherapeutics that are effective against both diabetes and diabetic complications.     

Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives

A series of derivatives of Matijing-Su (MTS, N-(N-benzoyl-l-phenylalanyl)-O-acetyl-l-phenylalanol) was synthesized and evaluated for their anti-hepatitis B virus (HBV) activities in 2.2.15 cells. The IC₅₀ of compounds 9c (1.40 μM), 9g (2.33 μM) and 9n (2.36 μM), etc. and the selective index of 9n (45.93) of the inhibition on the replication of HBV DNA were higher than those of the positive control lamivudine [41.59, (IC₅₀: 82.42 μM)]. Compounds 11d, 12a and 12e also exhibited significant anti-HBV activities.     

牡蛎多糖体外对HepG2.2.15细胞分泌HBsAg、HBeAg的影响

目的 探讨牡蛎多糖体外抗乙型肝炎病毒(HBV)的作用.方法 采用HepG2.2.15细胞为体外细胞模型,给予不同浓度牡蛎多糖进行混合培养,作用9d后收集上清液,用ELISA法测定上清液中HBsAg、HBeAg的水平,观察药物对HepG2.2.15细胞分泌病毒杭原的影响,同时以MTT法检测药物在体外对HepG2.2.15细胞生长的抑制作用.结果 牡蛎多糖浓度在0.1～1 000 μg/mL时,对细胞无明显的毒性作用;牡蛎多糖可明显抑制HBsAg、HBeAg的分泌,其半数有效浓度( IC50)分别为362.2、558.6 μg/mL,治疗指数(TI)为＞27.6和＞17.9.结论 牡蛎多糖体外具有一定的抗HBV作用.     

Synthesis and in vitro anti-hepatitis B virus activity of six-membered azanucleoside analogues

Fifteen novel six-membered azanucleoside derivatives were prepared and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in human hepatoblastoma-derived liver Hep-G2 cells. The most potent compound 16b with an IC(50) value of 2.74μg/mL (lower than 3TC) and a SI value of 13.5 was disclosed. The key synthetic steps involved the rearrangement of lactones (which were readily obtained from monosaccharides) and the Lewis acid-catalyzed condensation of nucleobases with azasugar donors. Using the versatile acetylated azasugar donors, azanucleosides covering three types of azasugars and four types of natural nucleobases were successfully obtained. The experimental results showed that some six-membered azanucleosides may find applications in the discovery of new anti-viral agents.     

Anti-HBV agents. Part 2: Synthesis and in vitro anti-hepatitis B virus activities of alisol A derivatives

Chemical modifications were performed on hydroxyl groups at C-11,23,24,25 positions and C-13(17) double bond of alisol A for structure–activity relationship study. Forty-one derivatives of alisol A were synthesized and assayed for their in vitro anti-hepatitis B virus (HBV) activities and cytotoxicities. Of them, 14 compounds were active against HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) secretion in HepG 2.2.15 cells, and the most promising compound 25 exhibited high activities against secretion of HBsAg (IC₅₀ = 0.028 mM), HBeAg (IC₅₀ = 0.027 mM) and remarkable selective indices (SI_HBsAg >90, SI_HBeAg >93).     

Synthesis and in vitro anti-hepatitis B virus activities of 4-aryl-6-chloro-quinolin-2-one and 5-aryl-7-chloro-1,4-benzodiazepine derivatives

A series of 4-aryl-6-chloro-quinolin-2-ones and 5-aryl-7-chloro-1,4-benzodiazepine were synthesized and assayed for their in vitro anti-hepatitis B virus activities and cytotoxicities for the first time. Some of the tested compounds were active against HBsAg and HBeAg secretion in Hep G2.2.15 cells. Compound 5c showed IC(50) of 0.074 and 0.449 mM on HBsAg and HBeAg secretions, respectively, which were 10 times higher than that of its analog 4c and led to better selective index (SI) values (SI=23.2 and 3.4, respectively).     

Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups

A series of benzimidazole-5-carboxylic acid alkyl ester derivatives carrying amide or amidine substituted methyl or phenyl groups at the position C-2 were synthesised and evaluated for antibacterial and antifungal activities against S. aureus, methicillin resistant S. aureus (MRSA), S. faecalis, methicillin resistant S. epidermidis (MRSE), E. coli and C. albicans. The results showed that while all simple acetamides are essentially inactive, aromatic amides and amidines have potent antibacterial activities. Aromatic amidine derivatives 13 f-h exhibited the best inhibitory activity with 1.56-0.39 microg/mL MIC values against MRSA and MRSE.     

Synthesis and in vitro anti-hepatitis B virus activity of 6H-[1]benzothiopyrano[4,3-b]quinolin-9-ols

A series of novel 6H-[1]benzothiopyrano[4,3-b]quinoline derivatives were prepared and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in human hepatoblastoma-derived liver Hep-G2 cells. Compounds 10g, 10h, 10j, 10l and 10o were found to be potent anti-HBV compounds with IC₅₀ values less than 50 μM. The most promising compound was 10l, with an IC₅₀ value of 14.7 μM and a SI value of 12.4. This is the first report of the anti-HBV effects of 6H-[1]benzothiopyrano[4,3-b] quinolin-9-ols.     

Synthesis and cytotoxic and analgesic activities of some 1, 5-diaryl-3-ethoxycarbonylpyrrole derivatives

Some 1,5-diaryl-3-ethoxycarbonyl-2-methylpyrrole derivatives were obtained by reacting 1-aryl-3-ethoxycarbonylpent-1,4-diones and a suitable aniline derivative or sulfanilamide under Paal-Knorr pyrrole synthesis conditions. The cytotoxicity of the compounds was tested and all compounds, except for compound 2 h, showed a time-dependent increase in cytotoxic activity. Analgesic activities of the compounds were determined by using the tail-flick and tail-immersion methods; some of the compounds showed potent analgesic activity.     

Synthesis and cytotoxic and analgesic activities of some 1, 5-diaryl-3-ethoxycarbonylpyrrole derivatives

Some 1,5-diaryl-3-ethoxycarbonyl-2-methylpyrrole derivatives were obtained by reacting 1-aryl-3-ethoxycarbonylpent-1,4-diones and a suitable aniline derivative or sulfanilamide under Paal-Knorr pyrrole synthesis conditions. The cytotoxicity of the compounds was tested and all compounds, except for compound 2 h, showed a time-dependent increase in cytotoxic activity. Analgesic activities of the compounds were determined by using the tail-flick and tail-immersion methods; some of the compounds showed potent analgesic activity.     

Synthesis, in vitro anti-HIV and anti-hepatitis B activities and pharmacokinetic properties of amphiphilic heterodinucleoside phosphates containing ddC and AZT.

Amphiphilic heterodinucleoside phosphates containing AZT and ddC as antiviral monomer were synthesized according to the hydrogenphosphonate method and evaluated in vitro against HIV. dT-N4-pamddC was the most active (IC50 = 40 microM, EC50 = 80 nM) and least toxic (TI = 524) dimer and it exhibited also strong antiviral effects against eight AZT-resistant HIV strains. The ddC-containing heterodimers additionally inhibited HBV replication by 50-80% at 50 microM in Hep G2 2.2.15 cells.     

Synthesis and antituberculosis activity of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives

New series of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 3a-t, 1-methyl-5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones 4a-y and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones 5a-m were synthesized. The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. The new 5-methyl/trifluoromethoxy-1H-indole-2,3-dione derivatives, along with previously synthesized 5-methyl-1H-indole-2,3-dione 3-thiosemicarbazones 6a-l, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. 5-Methyl-1H-indole-2,3-dione 3-thiosemicarbazones (3b, 3d, 3f, 6c, 6d, and 6f), 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazones (3q-s) and 5-trifluoromethoxy-1-morpholinomethyl-1H-indole-2,3-dione 3-thiosemicarbazones (5e and 5j-l) were found to be the most potent inhibitors of M. tuberculosis growth described in this study.     

Anti HIV-1 agents 5: Synthesis and anti-HIV-1 activity of some N-arylsulfonyl-3-acetylindoles in vitro

In continuation of our program aimed at the discovery and development of compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 21N-arylsulfonyl-3-acetylindole analogs (2a–u) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among of all the analogs, several compounds exhibited significant anti-HIV-1 activity, especially N-phenylsulfonyl-3-acetyl-6-methylindole (2j) and N-(p-ethyl)phenylsulfonyl-3-acetyl-6-methylindole (2n) showed the most potent anti-HIV-1 activity with EC₅₀ values of 0.36 and 0.13 μg/mL, and TI values of >555.55 and 791.85, respectively. It demonstrated that introduction of the acetyl group at the 3-position of N-arylsulfonyl-6-methylindoles could generally lead to the more potent analogs.     

Synthesis and the biological evaluation of arylnaphthalene lignans as anti-hepatitis B virus agents

We have previously shown that helioxanthin can suppress human hepatitis B virus gene expression. A series of helioxanthin analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Modifications at the lactone rings and methylenedioxy unit of helioxanthin can modulate the antiviral activity. Among them, compound 32 is the most effective anti-HBV agent. Compound 32 can suppress the secretion of viral surface antigen and e antigen in HepA2 cells with EC₅₀ values of 0.06 and 0.14 μM, respectively. Compound 32 not only inhibited HBV DNA with wild-type and lamivudine-resistant strain but also suppressed HBV mRNA, core protein and viral promoters. In this study, a full account of the preparation, structure–activity relationships of helioxanthin analogues, and the possible mechanism of anti-HBV activity of this class of compounds are presented. This type of compounds possesses unique mode of action differing from existing therapeutic drugs. They are potentially new anti-HBV agents.     

Synthesis and biological activity of 5',9-anhydro-3-purine-isonucleosides as potential anti-hepatitis C virus agents

In order to study structure-activity relationships among the derivatives and congeners of 5',9-anhydro-3-(beta-D-ribofuranosyl)xanthine for anti-hepatitis C virus activity, a series of 5',9-anhydro-purine-isonucleosides with a substituent (s) at 6- or/and 8-position of the purine moiety were synthesized, and their anti-hepatitis C virus activity and cytotoxicity were evaluated and discussed.     

Synthesis and acrosin inhibitory activities of substituted ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives

A series of novel ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives were designed and synthesized and their in vitro acrosin inhibitory activities were evaluated. Most of the compounds exhibited acrosin inhibitory activities. Among them, three compounds (5l, 5n, and 5v) were more potent than that of the control TLCK. These provide a new structural type for the development of novel contraceptive acrosin inhibitory agents.     

A QSAR study on some series of anti-hepatitis B virus (HBV) agents

A quantitative structure-activity relationship (QSAR) study has been made on some series of anti-hepatitis B virus (HBV) agents, namely, a series of novel bis(L-amino acid) ester prodrugs of 9-[2--(phosphonomethoxy)ethyl]adenine, a similar series of compounds comprising of 2- amino-6-arylthio-9-[2-(phosphonoethoxy)ethyl] purine bis(2,2,2- trifluoroethyl) esters, and a series of 1-isopropylsulfonyl-2-amine benzimidazoles. In each case significant correlations are found between the anti-HBV potencies and some physicochemical and steric properties of the compounds, indicating that for the first two series the activity is controlled by the hydrophobic and the bulk properties of the molecules and, for the third series, the steric and hydrogen bonding properties of compounds are crucial for their anti-HBV potency.