Design, synthesis and preliminary pharmacological evaluation of new piperidine and piperazine derivatives as cognition-enhancers

A series of 2-oxopiperazine, 4-aminomethyl-, 3-amino- and 3-aminomethylpiperidine analogues of DM235 (sunifiram) and MN19 (sapunifiram), two previously reported potent cognition-enhancers, have been synthesized and tested in the mouse passive-avoidance test. The compounds display minimal effective doses in the range 0.3-10mg/kg. Although the new substances do not show improved activity when compared to the parent compounds, some useful information has been obtained to understand structure-activity relationships. In addition, the 3-aminopiperidine moiety appears to be a promising scaffold to synthesize new drugs endowed with cognition-enhancing activity.     

Synthesis and antiproliferative activity of new 2-glyco-3-nitro-2H-chromenes

3-nitro-2H-chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2H-chromenes have been prepared by one-pot oxa-Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as catalyst. The antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activities are in the low micromolar range and that some of them are more effective than the standards.     

Synthesis and neuropharmacological evaluation of 2-aryl- and alkylapomorphines

A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and characterized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several hitherto unknown compounds as well. The pharmacological profile of the previously published and the novel 2-alkyl- and arylapomorphines has been determined with the application of in vitro and in vivo techniques. For 2-phenyl- (2) and 2-(4-hydroxyphenyl)apomorphines (3) the superior dopamine agonist profile has been confirmed and for the novel compounds some remarkable results have been observed.     

Synthesis and antiviral activity against tobacco mosaic virus and 3D-QSAR of alpha-substituted-1,2,3-thiadiazoleacetamides

A series of alpha-substituted-1,2,3-thiadiazoleacetamides were prepared and tested in vitro against tobacco mosaic virus. The preliminary bioassays indicated that some of the new compounds are good as compared to the commercial pesticide Virus A at 500 mg/L, and the activity was influenced by the nature of the substituents. 3D-QSAR models were established based on the antiviral activity of the compounds. It has also been found that some of the new compounds also exhibit significant anti-HBV activity in human hepatoblastoma-derived liver Hep-G2 cells.     

Etude chimio-taxonomique dans le genre cistus

The composition of 3 species of genus Cistus L. has been analysed and compared: C. labdaniferus L. contains essentially compounds of labdane type, namely labdane-8, 15, 19-triol whose structure has been confirmed; C. monspeliensis L. contains almost exclusively compounds having a new squeleton, the cistane, with a cis-junction of A and B; no cyclic diterpenes have been isolated from C. salvifolius L. which has been found rich in unsaturated aliphatic acids one of which is a mono conjugated triethylenic acid.     

1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.     

Synthesis and biological properties of new 5-nitroindazole derivatives

A series of new 3-alkoxy- or 3-hydroxy-1-[omega-(dialkylamino)alkyl]-5-nitroindazoles have been synthesized and their trichomonacidal, antichagasic and antineoplastic properties studied. Five derivatives (5, 6, 8, 9 and 17) showed remarkable trichomonacidal activity against Trichomonas vaginalis at 10 microg/mL concentration. Three compounds (8, 10, 11) exhibited interesting antichagasic activity and these same compounds moderate antineoplastic activity against TK-10 and HT-29 cell lines. Unspecific cytotoxicity against macrophages has also been evaluated and only compounds 9, 10 and 11 resulted cytotoxic at the higher dose evaluated (100 microg/mL), loosing cytotoxicity at lower doses. QSAR studies have been carried out. X-ray crystallographic study of compound 8 has been performed.     

Efficient regioselective chemical modifications of maltotriose: an easy access to oligosaccharidic scaffold

Regioselective chlorination of fully unprotected maltotriose has given in high yield 1^I,2^I-III,3^I-III,4^III-octa-O-acetyl-6^I-III-trichloro-6^I-III-trideoxymaltotriose. Moreover, regioselective ditritylation of methyl β-maltotrioside has provided the two regioselectively C₆-disubstituted trisaccharides. Selective deprotection of these new compounds gives the corresponding diol and halogenated analogues, respectively, in good yield. All compounds have been completely characterized and the substitution pattern in the oligosaccharidic sequence has been elucidated. A new family of amphiphilic carbohydrates, namely the 6-deoxy-6-alkylthiomaltotriose derivatives, bearing either two or three thioalkyl hydrophobic chains, respectively, has been synthesized. Critical micellar concentration (CMC) values as well as the antimicrobial properties have been evaluated for amphiphilic compounds.     

Structure and stereochemistry of limonoids of Cabralea eichleriana

From Cabralea eichleriana seeds, the following compounds have been isolated: cabraleone, cabraleadiol, fissinolide, 3-deacetylfissinolide, gedunin, 7-deacetoxy-7-oxygedunin, 7-deacetoxy-7-hyd-roxygedunin, methyl angolensate, and three new compounds, 7-deacetoxy-7-hydroxyphotogedunin, cabralin, and isocabralin. Cabralin has also been obtained by photolysis of fissinolide.     

1-Oxo-3-substitute-isothiochroman-4-carboxylic acid compounds: Synthesis and biological activities of FAS inhibition

A new series 1-oxo-3-substitute-isothiochroman-4-carboxylic acid compounds have been designed and synthesized. Screening of these molecules for FAS inhibition in vitro has indicated that compounds 2c and 2d showed more effective FAS inhibition activities and higher therapeutic index than C75.     

Microwave assisted synthesis of N-arylphthalamic acids with hyperlipidemic activity

A series of substituted N-arylphthalamic acids 3a-i has been synthesized by the reaction of phthalic anhydride 1 and aryl- or heterocyclic amines 2a-i, in the absence of solvents, in a domestic microwave oven. The formation of nine N-arylphthalamic acids was accomplished in 1-3 min giving excellent yields for compounds 3a-g, but moderate yield of compounds 3h and 3i, respectively. Compounds 3h and 3i are new. Interestingly, N-arylphthalamic acids 3a-i induced hyperlipidemia in Swiss white mice and also increased animals' body weight.     

Potent inhibition of bacterial neuraminidase activity by pterocarpans isolated from the roots of Lespedeza bicolor

Bacterial neuraminidase has been highlighted as a key enzyme for pathogenic infection and sepsis. Six pterocarpans displaying significant levels of neuraminidase inhibitory activity were isolated from the root bark of Lespedeza bicolor. The isolated compounds were identified as three new pterocarpans (1-3) together with known compounds erythrabyssin II (4), lespebuergine G4 (5), and 1-methoxyerythrabyssin II (6). The new compounds were characterized as bicolosin A (1), bicolosin B (2), and bicolosin C (3). All compounds inhibited bacterial neuraminidase in a dose-dependent manner with significant inhibition (IC(50)=0.09-3.25 μM). All neuraminidase inhibitors screened were found to exhibit noncompetitive kinetics. The three most potent neuraminidase inhibitors (1, 3 and 6) feature a methoxy substitution on C-1.     

Steroidal and phenolic constituents of Lilium speciosum.

Phytochemical examination of the fresh bulbs of Lilium speciosum forma vestale has led to the isolation of a new phenolic glycoside and a new steroidal saponin. The respective structures of the new compounds have been shown by spectral analysis to be 6'-O-feruloylsucrose and (25R,26R)-26-methoxyspirost-5-en-3 beta-o1 3-O-alpha-L-rhamnopyranosyl-(1----2)-beta-D-glucopyranoside. Several known phenolic glycosides and saponins have also been isolated and identified.     

Isolation, structural elucidation, and neuroprotective effects of iridoids from Valeriana jatamansi

Two new iridoids, jatadoids A (1) and B (2), and two known compounds (3 and 4) were isolated from Valeriana jatamansi. Their structures were elucidated on the basis of extensive spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, 1D and 2D NMR). Compound 1 possessed an isovaleroxy group at the C-3 position that has previously been unreported in the class of iridoids. Four compounds were evaluated and compounds 1 and 3 showed moderate neuroprotective effects against MPP⁺-induced neuronal cell death in human dopaminergic neuroblastoma SH-SY5Y cells.     

Synthesis and structure-activity relationships for biphenyl H3 receptor antagonists with moderate anti-cholinesterase activity

The combination of antagonism at histamine H(3) receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4'-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H(3)-antagonists. Starting from these premises, the current work presents an expanded series of histamine H(3) receptor antagonists, characterized by a central 4,4'-biphenyl scaffold, where the structure-activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined. The steric properties and basicity of the terminal groups were modulated in symmetrical compounds, carrying identical substituents, and in asymmetrical compounds, having a piperidine ring at one end and different groups at the other. The length of the linker connecting the biphenyl scaffold to the terminal groups was also modulated. Binding studies at rat and human H(3) receptors evidenced the highest binding affinities for di-basic compounds, in the order of nM concentrations, and that the steric requirements for the two terminal groups are different. Many potent compounds showed good selectivity profiles over the other histamine receptors. Interestingly, some derivatives displayed a moderate ability to inhibit rat brain cholinesterase, for example compound 12 (1-[2-(4'-piperidinomethyl-biphenyl-4-yl)ethyl]piperidine) has a pIC(50)=5.96 for cholinesterase inhibition and high H(3) receptor binding affinity and antagonist potency (pK(i)=8.70; pK(B)=9.28). These compounds can be considered as rigid analogs of a recently reported class of dual-acting compounds and as a promising starting point for the design of new H(3)-antagonists with anti-cholinesterase activity.     

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite.     

1-aryl-6,7-methylenedioxy-3H-quinazolin-4-ones as anticonvulsant agents

A set of novel 1-aryl-6,7-methylenedioxy-3H-quinazolin-4-(thi)ones (3a–f) has been designed and screened as anticonvulsant agents in DBA/2 mice. The new compounds are provided with anticonvulsant properties comparable to those of GYKI 52466. To clarify the mode of action, their affinity for the quinazolinone/2,3-benzodiazepine site of the AMPA receptor complex has been assayed.