Three isoflavanones with cannabinoid-like moieties from Desmodium canum

Three further derivatives of 5,7,2',4'-tetrahydroxy-6-methyl isoflavanone have been isolated from the root extract of Desmodium canum and assigned the structures 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(1a,2,3,3a,8b,8c-hexahydro-6-hydroxy-1,1,3a-trimethyl-1H-4-oxabenzo[f]cyclobut[c,d]inden-7-yl)-4H-1-benzopyran-4-one (1) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(6a,7,8,10a-tetrahydro-3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl)-4H-1-benzopyran-4-one (2) 2,3-dihydro-5,7-dihydroxy-6-methyl-3-(3-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-2-yl) 4H-1-benzopyran-4-one (3). The three compounds and the previously isolated chromene 4 all derive from the geranylated precursor 5 by a series of cannabinoid-like oxidative rearrangements.     

Synthesis and structure elucidation of novel fused 1,2,4-triazine derivatives as potent inhibitors targeting CYP1A1 activity

Synthesis and structure elucidation of new series of novel fused 1,2,4-triazine derivatives 3a-3f, 4a-4i and 6a-6b and their inhibitory activities are presented. Molecular structures of the synthesized compounds were confirmed by (1)H NMR, (13)C NMR, MS spectra and elemental analyses. X-ray crystallographic analysis was performed on 2-acetyl-8-(N,N-diacetylamino)-6-(4-methoxybenzyl)-3-(4-methoxy-phenyl)-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 3d and 2-acetyl-8-(N-acetylamino)-6-benzyl-3-(4-chlorophenyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 4e to secure their structures. The inhibitory effect of these compounds toward the CPY1A1 activity was screened to determine their potential as promising anticancer drugs. Our data showed that compounds 4e, 5a, 5b and 6b possess the highest inhibitory effects among all tested compounds. Furthermore, analysis of triazolotriazine derivatives docking showed that these compounds bind only at the interface of substrate recognition site 2 (SRS2) and (SRS6) at the outer surface of the protein. Amino-acids ASN214, SER216 and ILE462 participate in the binding of these compounds through H-bonds.     

1,2,4-Triazino-[5,6b]indole derivatives: effects of the trifluoromethyl group on in vitro antimalarial activity

In an attempt to search for new and alternative antimalarial agents, a series of unsubstituted and 6-trifluoromethyl-1,2,4-triazino[5,6b]indole and 5H-1,2,4-triazolo[1',5',2,3]-1,2,4-triazino[5,6b]indole derivatives were synthesized and their chemical structures confirmed by 1H NMR and 13C NMR, elemental, IR and mass spectrophotometric analyses. The in vitro antimalarial activities of these compounds were evaluated against the chloroquine-sensitive (D10) and the chloroquine-resistant (RSA11) strains of Plasmodium falciparum. The 1,2,4-triazino[5,6b]indole derivatives (4, 6 and 8) with a trifluoromethyl group at position 6 exhibit increased in vitro activity when compared to the unsubstituted analogues, which are all devoid of activity. The presence of the trifluoromethyl group in the 5H-1,2,4-triazolo[1',5',2,3]-1,2,4-triazino[5,6b]indole ring system leads to compounds with diminished antimalarial activity when compared to the corresponding unsubstituted analogues. The compounds associate with ferriprotoporphyrin IX and interact with DNA to more or less the same extent.     

Discovery and structure-activity relationship of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a new series of potent apoptosis inducers

We report the discovery and SAR study of a series of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as potent inducers of apoptosis. N-(3-Acetylphenyl)-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine (2) was discovered through our cell- and caspase-based HTS assays as an inducer of apoptosis. Compound 2 is active against cancer cells derived from several human solid tumors, with EC(50) values ranging from 400 to 700 nM. SAR study of hit 2 led to the discovery of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a novel series of potent apoptosis inducers, with 1,3-dimethyl-N-(4-propionylphenyl)-1H-pyrazolo[3,4-b]quinolin-amine (6b) having EC(50) values ranging from 30 to 70 nM in cancer cells. These compounds also demonstrated potent activity in the cell growth inhibition assay, with GI(50) values of 16-42 nM for compound 6b.     

Indoline and piperazine containing derivatives as a novel class of mixed D(2)/D(4) receptor antagonists. Part 1: identification and structure-activity relationships

Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported.     

Potential inhibitors of angiogenesis. Part II: 3-(azolylmethylene)-2,3-dihydrobenzo[b]furan-2-ones

The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)-2,3-dihydrobenzo[b]furan-2-ones 8-10 and 3-(3,5-dimethylpyrrol-2-ylmethylene)-2,3-dihydrobenzo[b]furan-2-one 11, analogues of SU-5416, as potential inhibitors of angiogenesis, are reported. Compounds 8 and 11 were prepared by a Knoevenagel reaction starting from 2-hydroxyphenylacetic acid 2 and 4-formylimidazole 5 or 2-formyl-3,5-dimethylpyrrole 7, followed by acid-catalysed cyclodehydration. For compounds 9 and 10, an alternative method was used; it consisted in carrying out the Knoevenagel reaction with the 2,3-dihydrobenzo[b]furan-2-ones 3 and 4. The antiangiogenic activity of these compounds was evaluated in the three-dimensional in vitro rat aortic rings test at 1microM. At this concentration, compound 11 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density index at 1 microM of 11 and SU-5416 were 30 +/- 10 and 22 +/- 4% of control, respectively.     

Indole alkoloids from Nauclea officinalis with weak antimalarial activity

Five indole alkaloids (naucleofficines A-E) were isolated from the stems (with bark) of Nauclea officinalis: (E)-2-(1-beta-d-glucopyranosyloxybut-2-en-2-yl)-3-(hydroxymethyl)-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (1), (E)-1-propenyl-12-beta-d-glucopyranosyloxy-2,7,8-trihydro-indolo[2,3-a]pyran[3,4-g]quinolizin-4,5(13H)-dione (2), (E)-2-(1-hydroxybut-2-en-2-yl)-11-beta-d-glucopyranosyloxy-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (3), (E)-1-propenyl-4-hydroxy-2,4a,7,8,13b,14,14a-hepthydro-(4alpha,4abeta,13balpha,14abeta)indolo[2,3-a]pyran[3,4-g]quinolizin-5(13H)-one (4) and 1-(1-hydroxyethyl)-10-hydroxy-7,8-dihydro-indolo[2,3-a]pirydine[3,4-g]quinolizin-5(13H)-one (10-hydroxyangustoline) (5), together with two known compounds, naucleidinal (6) and angustoline (7). All of the structures of the seven compounds above were elucidated by spectroscopic methods including use of 1D- and 2D-NMR spectroscopic analyses. Compounds 2 and 3 are rare examples of monoterpene indole alkaloids with a glucopyranosyloxy group attached to position C-12. In vitro activity screening of the above seven compounds showed weak to moderate inhibitory activity against Plasmodium falciparum.     

Furanonaphthoquinones,atraric acid and a benzofuran from the stem barks of Newbouldia laevis

The series of naturally occurring furanonaphthoquinones is extended by identification of the derivatives 2-(1'-methylethenyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione and 2-(1'-methylethenyl)-7-hydroxynaphtho[2,3-b]furan-4,9-dione. They are accompanied in the stem barks of Newbouldia laevis by the known analogues 5-hydroxy-dehydro-iso-alpha-lapachone, 2-acetyl-5-hydroxynaphtho[2,3-b]furan-4,9-dione and 2-(1'-methylethenyl)naphtho[2,3-b]furan-4,9-dione along with the rare atraric acid and the new 2-(1'-methylethenyl)-6-hydroxy-2,3-dihydrobenzofuran. The structures of these compounds were established from spectroscopic studies.     

Antiviral 2,5-disubstituted imidazo[4,5-c]pyridines: further optimization of anti-hepatitis C virus activity

Substituted 5-benzyl-2-phenyl-5H-imidazo[4,5-c]pyridines represent a novel class of compounds with activity against pestiviruses and the hepatitis C virus (HCV). Several series of analogues with modifications of the substituents in positions 2 and 5 were prepared. These efforts resulted in the discovery of several compounds with potent antiviral activity of which 2-(2,3-difluorophenyl)-5-[4-(trifluoromethyl)benzyl]-5H-imidazo[4,5-c]pyridine (46) was most potent against HCV (EC(50) of 0.10 microM and a selectivity index of 1080).     

Antibacterial bromophenols from the marine red alga Rhodomela confervoides

Two bromophenols, together with three known compounds, were isolated from the methanolic extract of the marine alga, Rhodomela confervoides. By means of MS and NMR spectroscopic analyses, they were identified as 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5-(hydroxymethyl) 1,2-benzenediol (1) and 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5- (ethoxymethyl) 1,2-benzenediol (2). Three known compounds were also isolated, namely 3-bromo-4-[2,3-dibromo-4,5-dihydroxyphenyl] methyl-5-(methoxymethyl) 1,2-benzenediol (3), 4,4'- methylenebis [5,6-dibromo-1,2-benzenediol] (4) and bis (2,3-dibromo-4,5-dihydroxybenzyl) ether (5). Compound 5 was the most active against five strains of bacteria with the MIC less than 70 microg/ml, while compounds 2, 3 and 4 exhibited moderate activity.     

Oxadiazole mannich bases: synthesis and antimycobacterial activity

A series of oxadiazole mannich bases were synthesized by reacting oxadiazole derivatives, dapsone and appropriate aldehyde in the presence of methanol. The synthesized compounds were evaluated for antimycobacterial activity against M. tuberculosis H(37)Rv and INH resistant M. tuberculosis. Among the synthesized compounds, compound (4) 3-{2-furyl[4-(4-{2-furyl[5-(2-naphthyloxymethyl)-2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl]methylamino}phenylsulfonyl)anilino]methyl}-5-(2-naphthyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thione was found to be the most promising compound active against M. tuberculosis H(37)Rv and isoniazid (INH) resistant M. tuberculosis with Minimum inhibitory concentration (MIC) 0.1 microM & 1.10 microM respectively.     

Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues

The synthesis and preliminary results for acetylcholinesterase and butyrylcholinesterase inhibition activity of a series of pyrano[2,3-b]quinolines (2, 3) and benzonaphthyridines (5, 6) derivatives are described. These molecules are tacrine-like analogues which have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyrans and 6-amino-5-cyanopyridines]-3-carboxylates via Friedlander condensation with selected ketones. These compounds showed moderate acetylcholinesterase inhibition activity, the more potent (2e, 5b) being 6 times less active than tacrine. The butyrylcholinesterase activity of some of these molecules is also discussed.     

Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.     

Novel cyano- and amidino-substituted derivatives of thieno[2,3-b]- and thieno[3,2-b]thiophene-2-carboxanilides and thieno[3',2':4,5]thieno- and thieno[2',3':4,5]thieno [2,3-c]quinolones: synthesis, photochemical synthesis, DNA binding, and antitumor evaluation

A series of cyano- and amidino-substituted derivatives of thieno[2,3-b]- and thieno[3,2-b]thiophene-2-carboxanilides and their 'cyclic' derivatives (quinolones) were synthesized. 'Cyclic' compounds displayed a rather strong and differential antiproliferative effect on various cell lines, while the 'acyclic' amidino-substituted compounds were much more active, but showing mostly non-differential cytotoxicity, whereas cyano-substituted compounds (2a,b) produced a strikingly strong effect selectively on HeLa and Hep-2 cell lines. Antiproliferative activity of 'cyclic' derivatives is very likely caused by intercalation into DNA, while their 'acyclic' analogues use other target(s) and/or mechanisms of action.     

Synthesis and anti-HIV-1 activity of 4-substituted-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues

Three novel 4-subsituted-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues were designed, synthesized, and tested for their anti-HIV-1 activity. Initial biological studies indicated that among these pyrrolo[2,3-d]pyrimidine ribonucleoside analogues, 4-amino-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 10 exhibited the most potent anti-HIV-1 activity (EC(50)=0.5±0.3 μM), while 4-hydroxy-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d] pyrimidine 9 and 4-amino-5-fluoro-7-(2'-deoxy-2'-fluoro-4'-azido-β-D-ribofuranosyl)pyrrolo[2,3-d] pyrimidine 11 showed moderate activity (EC(50)=13±8 and 5.4±0.3 μM, respectively). The cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for any of these compounds with concentrations up to 25 μM.     

Glucose-6-phosphatase catalytic enzyme inhibitors: synthesis and in vitro evaluation of novel 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines

The discovery of the first class of potent glucose-6-phosphatase catalytic site inhibitors, substituted 4,5,6,7-tetrahydrothieno[3,2-c]- and -[2,3-c]pyridines, is described. Optimisation of this series involved solution phase combinatorial synthesis and very potent compounds were prepared with IC50 values down to 140 nM. The structure activity relationship (SAR) of these compounds indicates that: a tetrahydrothieno[3,2-c]pyridine core ring system and the isomeric [2,3-c] system are equipotent and much better than the corresponding benzo analogue, 1,2,3,4-tetrahydro-isoquinoline. The 4-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a phenyl group, optionally substituted with a lipophilic 4-substituent, such as trifluoromethoxy or chloro. The 5-substituent of the tetrahydrothieno[3,2-c]pyridine ring has to be a substituted benzoyl; anisoyl and (E)-3-furan-3-ylacryloyl are the best of the investigated groups. Substitution in the benzoyl ortho position seems to be forbidden, whereas substitution in the meta position is tolerated only if a methoxy para substituent is present. These SAR findings were parallel to those obtained in the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine system. Enantioselectivity in enzyme recognition was observed and the activity resided in all cases only in one of the enantiomers.     

CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin-releasing hormone type 1 receptor antagonists.

A series of compounds related to N-butyl-N-ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (1, antalarmin) have been prepared and evaluated for their CRHR1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (delta-hydroxy or bis-beta-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]butan-1-ol (3), bearing a terminal hydroxyl group on an N-alkyl side-chain, showed the highest CRHR1 binding affinity among these compounds (K(i)=0.68 nM), and is one of the highest affinity CRHR1 ligands known. Compounds 3-5, and 8, which are likely to be less lipophilic than 1, have high CRHR1 affinity and may be valuable probes to further study the CRH system.     

Synthesis and cytotoxic evaluation of certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives

Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM).     

Synthesis, cytotoxicity, and anti-inflammatory evaluation of 2-(furan-2-yl)-4-(phenoxy)quinoline derivatives. Part 4

A number of 2-(furan-2-yl)-4-phenoxyquinoline derivatives have been synthesized and evaluated for anti-inflammatory evaluation. 4-[(2-Furan-2-yl)quinolin-4-yloxy]benzaldehyde (8), with an IC(50) value of 5.0 microM against beta-glucuronidase release, was more potent than its tricyclic furo[2,3-b]quinoline isomer 3a (>30 microM), its 4'-COMe counterpart 7 (7.5 microM), and its oxime derivative 13a (11.4 microM) and methyloxime derivative 13b (>30 microM). For the inhibition of lysozyme release, however, oxime derivative 12a (8.9 microM) and methyloxime derivative 12b (10.4 microM) are more potent than their ketone precursor 7 and their respective tricyclic furo[2,3-b]quinoline counterparts 4a and 4b. Among them, 4-[4-[(2-furan-2-yl)-quinolin-4-yloxy]phenyl]but-3-en-2-one (10) is the most active against lysozyme release with an IC(50) value of 4.6 microM, while 8 is the most active against beta-glucuronidase release with an IC(50) value of 5.0 microM. (E)-1-[3-[(2-Furan-2-yl)quinolin-4-yloxy]phenyl] ethanone oxime (11a) is capable of inhibiting both lysozyme and beta-glucuronidase release with IC(50) values of 7.1 and 9.5 microM, respectively. For the inhibition of TNF-alpha formation, 1-[3-[(2-furan-2-yl)quinolin-4-yloxy]phenyl]ethanone (6) is the most potent with an IC(50) value of 2.3 microM which is more potent than genistein (9.1 microM). For the inhibitory activity of fMLP-induced superoxide anion generation, 11a (2.7 microM), 11b (2.8 microM), and 13b (2.2 microM) are three of the most active. None of above compounds exhibited significant cytotoxicity.     

Phytochemicals from the stem wood of Sorbus lanata (D. Don.) Schauer

Three new phenolic compounds, sorlanin (4-(3-(hydroxymethyl)-5-methoxy-7-phenyl-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-2-methoxyphenol, 1), sorbanin (2-((3,5-dimethoxy-[1,1′-biphenyl]-4-yl)oxy)-1-(4-hydroxy-3-methoxyphenyl)propane-1,3-diol, 2) and sorbalanin (4-(3-(hydroxymethyl)-5,6-dimethoxy-2,3-dihydrobenzo[b][1,4]dioxino[2,3-g]benzofuran-2-yl)-2-methoxyphenol, 3), together with eight known compounds, polystachyol (4), isolariciresinol (5), dihydrodehydrodiconiferyl alcohol (6), tuberculatin (7), ovafolinin E (8), aucuparin (9), 2′-methoxyaucuparin (10), and tetracosyl-3-(3,4-dihydroxyphenyl)acrylate (11), were isolated from Sorbus lanata. The structures of these phytoconstituents were elucidated through extensive spectroscopic techniques, including UV, IR, 1D and 2D NMR, ESI-MS and HRESI-MS experiments. All the compounds except 9 and 10 were isolated for the first time from the genus Sorbus. The isolated compounds were also tested in DPPH radical scavenging reaction where compounds 6, 7, 10 and 11 showed significant activities with IC₅₀ values of 9.2, 11.7, 23.0 and 33.7 μM, respectively.