Substituted propanolamines and alkylamines derived from fluoxetine as potent appetite suppressants

A series of propanolamine and alkylamine analogues of fluoxetine (7-26, 28-31) were synthesized and assessed for their anorexigenic and antidepressant activities. Effect of various substituents at C-4 aryl position of fluoxetine has also been studied. Most of the propanolamine analogues (7-13, 16-26) displayed significant anorexigenic activity but interestingly they were devoid of antidepressant activity whereas anorexigenic as well as antidepressant activity was retained in the alkylamine series (28-31). Compounds 10 and 26 emerged as the most active compound and anorexigenic activity was better (83.67% and 82.45%) compared to fluoxetine (81.25%).     

Synthesis of tetrahydronaphthyl thioureas as potent appetite suppressants

A series of thiourea derivatives (7-23, 25-27) of 1-aminotetrahydronaphthalene (4) and 1-amino-2-hydroxytetrahydronaphthalene (5) were synthesized in single pot in 48-90% yield and evaluated for their anorexigenic activity. Among them compounds 10, 14, 15, 16 and 22 exhibited significant anorexigenic activity without any antidepressant effect and provided a new structural lead for appetite suppressants.     

Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.     

Synthesis and antidepressant-like activity evaluation of sulphonamides and sulphonyl-hydrazones

In this study a series of sulphonamides and sulphonyl hydrazones of maleimide, naphthalimide and phthalimide derivatives was synthesized. The antidepressant effect of these compounds was evaluated by the forced-swimming test in mice. The behavioural parameter observed in this test is a reduction in the immobility time, which is indicative of antidepressant activity. All compounds, except 8, 11 and 24, were active as antidepressants. The most active compound was the sulphonyl-hydrazone 10 which showed an activity of around 72.02% at 60 mg/kg, it thus being more active than imipramine (10mg/kg, ip), a commercial antidepressant. Other important results were obtained for the benzylnaphthalimide derivatives, the sulphonamides 21 and 22 showing activity of 64% at 10mg/kg, also being more active than imipramine. These results indicate that the sulphonamides and sulphonyl-hydrazone cyclic imide derivatives are potential compounds for use in the designing of new candidates for the treatment of depression.     

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.     

Glucagon: structure-function relationships investigated by sequence deletions

A series of glucagon analogues, des-(1-4)-glucagon, des-(5-9)-glucagon, des-(10-15)-glucagon, des-(16-21)-glucagon, des-(22-26)-glucagon and des-(27-29)-glucagon, were prepared by condensation of synthetic fragments and characterized biologically and immunologically. Fully synthetic glucagon was also characterized. The potencies with regard to glucagon receptor binding in purified rat liver plasma membranes were, in decreasing order: synthetic glucagon 108%, des-(1-4)-glucagon 5.7%, des-(27-29)-glucagon 0.92%, des-(5-9)-glucagon 0.47%, des-(10-15)-glucagon 0.0028%, des-(16-21)-glucagon 0.0017% and des-(22-26)-glucagon 0.00060% relative to that of natural porcine glucagon. Des-(27-29)-glucagon was the only analogue that activated the adenylate cyclase in rat liver plasma membranes or stimulated the lipolysis in isolated free fat cells from rat epididymal fat pad. The potencies were 0.16% and 0.20% of that of glucagon, respectively. Des-(1-4)-glucagon was a glucagon antagonist in the adenylate cyclase assay. The immunoreactivities of the glucagon analogues were determined with two commonly used anti-glucagon sera, K 5563 and K 4023, directed towards the C-terminus and some segment in the sequence 2-23, respectively. In the K 5563 assay, des-(27-29)-glucagon and des-(22-26)-glucagon had potencies of 0.0009% and less than 0.09% of that of glucagon, respectively. The remaining analogues had potencies varying from 45% to 141% of that of glucagon. In the K 4023 assay, the analogues showed a non-linear dilution effect. The combined results indicate a partition within the glucagon molecule with regard to receptor binding and adenylate cyclase activation. The region 10-26 appears to be the most important for receptor binding, whereas 1-4 is essential for adenylate cyclase activation. The C-terminal segment 27-29 is important for the maintenance of full receptor binding but non-essential for adenylate cyclase activation.     

Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents

A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space.     

Cytotoxic triterpenoid saponins from the fruits of Aesculus pavia L

Continued chemical investigation on the fruits of North American Aesculus pavia L. resulted in the isolation and identification of 13 polyhydroxyoleanene pentacyclic triterpenoid saponins, named aesculiosides IIe-IIk (1-7), and IIIa-IIIf (8-13), together with 18 known compounds: aesculiosides Ia-Ie (14-18), IIa-IId (19-22), IVa-IVc (23-25), 3-O-[beta-D-galactopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,15 alpha,16 alpha,21 beta,22 alpha,28-hexahydroxyolean-12-ene (26), 3-O-[beta-D-glucopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,16 alpha,21 beta,22 alpha,24 beta,28-hexahydroxyolean-12-ene (27), 3-O-[beta-D-galactopyranosyl(1-->2)]-alpha-L-arabinofuranosyl(1-->3)-beta-D-glucuronopyranosyl-21,22-O-diangeloyl-3beta,16 alpha,21 beta,22 alpha,28-pentahydroxyolean-12-ene (28), R(1)-barrigenol (29), scopolin (30), and 5-methoxyscopolin (31). The structures of these compounds were elucidated by spectroscopic and chemical analyses. Compounds 14-22 and 26-28 were tested in vitro for their activity against 59 cell lines from nine different human cancers including leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast. It was found that compounds with two-acyl groups at C-21 and C-22 had cytotoxic activity for all cell lines tested with GI(50) 0.175-8.71 microM, while compounds without acyl groups at C-21 and C-22 had weak or no cytotoxic activity. These results suggest that the acyl groups at C-21 and C-22 are essential for their activity.     

9-[(Hydroxymethyl)phenyl]adenines: new aryladenine substrates of adenosine deaminase

New phenyl adenine compounds 5-7 were synthesized as analogues of adenosine and studied for their adenosine deaminase (ADA) substrate activity. The 9-[(o-hydroxymethyl)phenyl]methyl]adenine 5 and 9-[(m-hydroxymethyl)phenyl]adenine 7 were deaminated by ADA, and 9-[(o-hydroxyethyl)phenyl]adenine 6 was not deaminated up to 7 days. The ADA substrates 5 and 7 were deaminated quantitatively to their inosine analogues in 10 and 6h, respectively.     

心钠素的结构与功能的研究

心钠素的结构与功能的研究王进,施薄涛（中国科学院上海生物化学研究所,２０００３１）关键词心钠素ＡＰＩＩＩ;类似物;舒张;利尿;降血压心钻素（ＡＮＰ,ａｔｒｉａｌｎａｔｒｉｕｒｅｔｉｃＰｅＰｔｉｄｅ）是ＤｅＢｏｌｄ在１９８１年发现的一种由大鼠心肌细胞分...     

Synthesis and antitumor activity of β-carboline 3-(substituted-carbohydrazide) derivatives

A series of β-carboline derivatives bearing a substituted-carbohydrazide moiety at C-3 were synthesized and evaluated for their antitumor activity against eight human cancer cell lines. The β-carboline N-(substituted-benzylidene)carbohydrazides showed, in general, a greater antitumor activity than their N-(alkylidene)carbohydrazide analogues. The N(9)-methylation of β-carboline N-(substituted-benzylidene) carbohydrazides resulted in a decrease of antitumor activity. Among compounds tested, the benzylidene-carbohydrazides 3, 4, 11, 13, 16, 21 and 22 were the most active, possessing IC(50) less than 10 μM for six of the eight tumor cell lines assayed. The derivative 4 displayed the most significant activity toward all tested cell lines, with a remarkable cytotoxicity against renal (786-0) cell lines (IC(50)=0.04 μM). Compound 4 was assayed for its in vivo antineoplastic activity in the Ehrlich solid carcinoma assay.     

Synthetic studies on glycosphingolipids from the parasite Echinococcus multilocularis.

Novel neutral glycosphingolipids isolated from the metacestodes of Echinococcus multilocularis by Persat, may be expected to be involved in host-parasite interactions. We have synthesized these glycosphingolipid analogues containing 2-branched fatty alkyl residues in place of ceramide. The glycosylation of galactosyl donors 4 and 5 with each of the acceptors 2 and 11 in the presence of N-iodosuccinimide (NIS)/TfOH, and the glycosylation of fucosyl donor 13 with acceptors 12 and 20 in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) gave the desired oligosaccharide derivatives at good yield. The fully per-O-acylated 2-(trimethylsilyl)ethyl glycosides 6, 15, 21, and 26 were converted to glycosylimidates 7, 16, 22, and 27, which were condensed with 2-(tetradecyl)hexadecanol and subsequently deacylated give four target glycosphingolipid analogues.     

Cytotoxicities, cell cycle and caspase evaluations of 1,6-diaryl-3(Z)-hexen-1,5-diynes, 2-(6-aryl-3(Z)-hexen-1,5-diynyl)anilines and their derivatives

Compounds 3, 6-7, 9-10, 15-17, and 20-21 showed growth inhibition effects on a full panel of 60 human cancer cell lines, and most of the average IC50 values of the indicated analogues were from < 0.01 to 96.6 microM, in which analogues 16 and 17 revealed the highest cytotoxic activity with the cancer cell lines at 10(-7) M concentration range. During the cell cycle analysis, a moderate to high apoptotic progress induction was shown by 3, 9, 16-17, and 20 compared with the control, which 2-(6-(2-thienyl)-3(Z)-hexen-1,5-diynyl)aniline 16 showed the highest apoptotic effect. Structures 16-17 displayed a significant G2/M phase arrest in the cell growth cycle compared with other derivatives, which the proportions of the G2/M phase cells were accumulated to 71.5% and 82.6%, respectively. Moreover, the colorimetric assay of 16-17 also provided advanced evidence to the relationship between the compounds and the caspase-3 enzyme, which was one of the major promoters of apoptotic effect.     

Tripeptide mimetics inhibit the 20 S proteasome by covalent bonding to the active threonines

Proteasomes play an important role in protein turnover in living cells. The inhibition of proteasomes affects cell cycle processes and induces apoptosis. Thus, 20 S proteasomal inhibitors are potential tools for the modulation of neoplastic growth. Based on MG132, a potent but nonspecific 20 S proteasome inhibitor, we designed and synthesized 22 compounds and evaluated them for the inhibition of proteasomes. The majority of the synthesized compounds reduced the hydrolysis of LLVY-7-aminomethylcoumarin peptide substrate in cell lysates, some of them drastically. Several compounds displayed inhibitory effects when tested in vitro on isolated 20 S proteasomes, with lowest IC(50) values of 58 nm (chymotrypsin-like activity), 53 nm (trypsin-like activity), and 100 nm (caspase-like activity). Compounds 16, 21, 22, and 28 affected the chymotrypsin-like activity of the beta5 subunit exclusively, whereas compounds 7 and 8 inhibited the beta2 trypsin-like active site selectively. Compounds 13 and 15 inhibited all three proteolytic activities. Compound 15 was shown to interact with the active site by x-ray crystallography. The potential of these novel inhibitors was assessed by cellular tolerance and biological response. HeLa cells tolerated up to 1 microm concentrations of all substances. Intracellular reduction of proteasomal activity and accumulation of polyubiquitinated proteins were observed for compounds 7, 13, 15, 22, 25, 26, 27, and 28 on HeLa cells. Four of these compounds (7, 15, 26, and 28) induced apoptosis in HeLa cells and thus are considered as promising leads for anti-tumor drug development.     

Pharmacophore identification of a specific CXCR4 inhibitor, T140, leads to development of effective anti-HIV agents with very high selectivity indexes

A polyphemusin peptide analogue, T22 ([Tyr(5,12), Lys7]-polyphemusin II), and its shortened potent analogues, T134 (des-[Cys(8,13), Tyr(9,12)]-[D-Lys10, Pro11, L-citrulline16]-T22 without C-terminal amide) and T140 [[L-3-(2-naphthyl)alanine3]-T134], strongly inhibit the T-cell line-tropic (T-tropic) HIV-1 infection through their specific binding to a chemokine receptor, CXCR4. T22 is an extremely basic peptide possessing five Arg and three Lys residues in the molecule. In our previous study, we found that there is an apparent correlation in the T22-related peptides between the number of total positive charges and anti-HIV activity or cytotoxicity. Here, we have conducted the conventional Ala-scanning study in order to define the anti-HIV activity pharmacophore of T140 (the strongest analogue among our compounds) and identified four indispensable amino acid residues (Arg2, Nal3, Tyr5, and Arg14). Based on this result, a series of L-citrulline (Cit)-substituted analogues of T140 with decreased net positive charges have been synthesized and evaluated in terms of anti-HIV activity and cytotoxicity. As a result, novel effective inhibitors, TC14003 and TC14005, possessing higher selectivity indexes (SIs, 50% cytotoxic concentration/50% effective concentration) than that of T140 have been developed.     

New N-pyridinyl(methyl)-N1-substituted-3-indolepropanamides acting as topical and systemic anti-inflammatory agents

N-Pyridinyl(methyl)-N1-substituted-3-indolepropanamides (17-32) were prepared starting from the corresponding acids and screened for their anti-inflammatory activity. Pharmacomodulation was carried out on the indole and amidic nitrogens by incorporation of substituents associated with higher potency in previously synthesized related 3-indolepropanamides series. In the inhibition of topical inflammation determined by reduction of ear thickness in the acute PMA mouse ear swelling test, high levels of activity (ID50 approximately 0.030 mMol kg(-1)) were noticed for the five propanamides 17, 21, 22, 27 and 31. A comparative study showed the positive influence of a methyl group at the indole nitrogen in the 4-pyridinyl sub-series (1 --> 21) and of a 4-fluorobenzyl group in the 3-pyridinylmethyl sub-series (19 --> 31), at least after oral administration. After topical application, although compounds 17, 21, 22, 27 and 31 exerted significant (50%) ear edema inhibition at 2 x 50 microg/ear, they remained less potent than 24,29 and 30 (almost 70% inhibition). Among these eight amides, only 17, 21, 22 and 27 showed a significant activity in the carrageenan rat paw aedema model at 0.2 mMol kg(-1). Finally, although less active than the N-(4-pyridinyl) amide 21, the N-4,6-dimethyl-2-pyridinyl derivatives 17 and 27 were devoid of the toxic effects observed with 21 and to a lesser extent with 22.     

Heterocyclic rimantadine analogues with antiviral activity

2-(1-Adamantyl)pyrrolidines 6, 7, 2-(1-adamantyl)piperidines 10, 12a–c, 15a,b and 2-(1-adamantyl)hexahydroazepines 19, 21, 22 were synthesized and tested for their antiviral activity against influenza A, B viruses and the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The synthetic procedure followed for the preparation of the parent piperidine 10 represents a general method for the synthesis of 2-alkyl- or cycloalkyl-substituted piperidine alkaloids. Parent aminoadamantanes 6, 10 and 19 contain the 1-aminoethyl pharmacophore group of rimantadine drug 2, extended into a saturated nitrogen heterocycle: pyrrolidine, piperidine and hexahydroazepine, respectively. The ring size effect in anti-influenza A activity was investigated. Rimantadine analogues 6 and 10 were, respectively, 6- and 4-fold more active than the drug Rimantadine 2, whereas the hexahydroazepine derivative 19 was inactive. Thus, enlargement from a 5-(pyrrolidine)- or 6-(piperidine)- to a 7-(hexahydroazepine)- membered heterocyclic ring dramatically reduced the anti-influenza virus A activity. Substitution of piperidine 10 with a dialkyaminoethyl group led to the active compounds 15a and 15b: compound 15a was active against influenza A virus whereas both 15a and 15b were active against HIV-1.     

Analysis of insecticidal Azadirachta indica A. Juss. fractions

As a result of chemical investigation on the ethanolic extract of fresh fruit coatings of Azadirachta indica A. Juss. (neem), twenty-seven compounds were identified in non-polar to less polar fractions which showed pesticidal activity determined by WHO method against Anopheles stephensi Liston. These identifications were basically made through GC-EIMS and were further supported by other spectroscopic techniques, including 13C NMR, UV and FTIR as well as retention indices. Thus sixteen n-alkanes, 1-16; three aromatics 2,6-bis-(1,1-dimethylethyl)-4-methyl phenol (17), 2-(phenylmethylene)-octanal (20), 1,2,4-trimethoxy-5-(1Z-propenyl)-benzene (27); three benzopyranoids 3,4-dihydro-4,4,5,8-tetramethylcoumarin (18), 3,4-dihydro-4,4,7,8-tetramethylcoumarin-6-ol (19), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta[g]-2-benzopyran (22); one sesquiterpene methyl-3,7,11-trimethyl-2E,6E,10-dodecatrienoate (21); three esters of fatty acids methyl 14-methyl-pentadecanoate (23), ethyl hexadecanoate (24), ethyl 9Z-octadecenoate (25) and one monoterpene 3,7-dimethyl-1-octen-7-ol (26) were identified. Except 6, 8, 24 and 25 all these compounds were identified for the first time from the pericarp and fifteen of these, 1-3, 7, 9, 10, 17-23, 26, 27, are hitherto unreported previously from any part of the tree. Although this tree is a rich source of various natural products, it is the first report of identification of mono- and sesquiterpenes 26 and 21 and a potent antioxidant, 17.     

Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores

A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues.     

Concise synthesis and antiviral activity of novel unsaturated acyclic pyrimidine nucleosides

Novel acyclic nucleoside analogues were designed and synthesized as open-chain analogues of neplanocin A. The coupling of the allylic bromide with pyrimidine bases using cesium carbonate afforded a series of novel acyclic nucleosides. The synthesized compounds 15-22 were evaluated for their antiviral activity against various viruses such as HIV, HSV-1, HSV-2, and HCMV.