Syntheses and antifungal activities of 1-[4-phenyl-2-(phenylthio or acyloxy)-n-butyl]-1H-imidazole derivatives]

The title compounds (4b, d-f, h-j) were prepared from 1-[4-(p-substituted phenyl)-2-chloro-n-butyl]-1H-imidazoles and the corresponding thiophenols or mercaptopyridines. Acyloxy compounds (5a-e) were prepared from alcohol (2b) and the corresponding acyl chlorides. In the antifungal activity test, p-tolyl compounds (4e, f) showed as good activity as butoconazole (4c).     

Synthesis and Antimicrobial Activity of Some New 2-(3-(4-Aryl)-1-phenyl-1H-pyrazol-4-yl) Chroman-4-ones

Seven new 2-(3-(4-aryl)-1-phenyl-1H-pyrazol-4-yl) chroman-4-ones (4a-4g) have been synthesized by cyclization of 2-hydroxychalcone analogues of pyrazole 3a-3g using conc. HCl in acetic acid. The structures of the compounds 4a-4g were established by the combined use of (1)HNMR, IR and mass spectra. All the seven compounds were tested in vitro for their antibacterial activity against two Gram positive bacteria namely Staphylococcus aureus and Bacillus subtilis and two Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa. The compounds 4b, 4c, 4e, 4f, 4g have displayed good antibacterial activity when compared with commercially available antibiotic, ciprofloxacin. These compounds also were screened for their antifungal activity against two ear pathogenic fungi, namely Aspergillus Niger and A. flavus. The compounds 4a, 4c, 4d, 4g exhibited good antifungal activity when compared with commercially available antifungal, fluconazole.     

Synthesis and anti-inflammatory evaluation of new substituted 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole derivatives

A series of heterocyclic derivatives including 1,2,4-triazole-3(4H)-one (3a,b), 1H-pyrazol-5(4H)-one (4,5), 1H-pyrazol-4-carbonitrile (7), pyridine-3-carbonitrile (8, 9a,b), pyrimidine-5-carbonitrile (10a,b), methylpyrimidin-2(1H)-one or thione (11a,b), pyrimidine-5-carboxylate (12a,b), quinazolin-5(6H)-one (13a,b) and indeno [1,2-d] pyrimidin-5-one (14a,b) moieties conjugated with 1,3-disubstituted pyrazole moiety were synthesized on reaction with semicarbazide, thiosemicarbazide, 3-amino-5-oxo-2-pyrazoline, cyanoacetohydrazide, 2-acetyl thiophene, p-chloroacetophenone, urea, thiourea and 1,3-dicarbonyl compounds, respectively, by using 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (2) as starting material. The structures of all the newly synthesized products have been established on the basis of analytical and spectral data. The anti-inflammatory screening showed that most of the obtained compounds were found to have significant anti-inflammatory activities with prostaglandin inhibition at a dose level of 2.5 and 5 mg/kg comparable to celecoxib as a reference control. The ulcer indices of all compounds are mainly in the safe level (UI = 2.10-4.27) except for compounds 9a and 14a, which were highly ulcerogenic.     

4-(3-coumarinyl)-4-thiazolin-2-one benzylidenehydrazones with antituberculosis activity

In this study a new series of 4-(3-coumarinyl)-4-thiazoline-2-one benzylidenehydrazones (3a-v) were synthesized by condensation of 3-(omega-bromoacetyl)coumarins (1a and 1b) with 1-substituted benzylidene-4-substituted thiosemicarbazides (2a-1). Structures of the title compounds were elucidated by elemental analyses and spectrometric data (UV, IR, 1H-NMR and EIMS). These new compounds and some previously reported compounds (1a-d) were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv. The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M. tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. 1b, 3b, 3e, 3h, 3o and 3p demonstrating activity in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460 and Alamar Blue assay (MABA). The most active compound was found to be 1b. The structure-activity relationships of the derivatives were investigated.     

3-(4-Aroyl-1-methyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamides as a new class of synthetic histone deacetylase inhibitors. 2. Effect of pyrrole-C2 and/or -C4 substitutions on biological activity

Previous SAR studies (Part 1: Mai, A.; et al. J. Med. Chem. 2003, 46, 512-524) performed on some portions (pyrrole-C4, pyrrole-N1, and hydroxamate group) of 3-(4-benzoyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide (1a) highlighted its 4-phenylacetyl (1b) and 4-cynnamoyl (1c) analogues as more potent compounds in inhibiting maize HD2 activity in vitro. In the present paper, we investigated the effect on anti-HD2 activity of chemical substitutions performed on the pyrrole-C2 ethene chains of 1a-c, which were replaced with methylene, ethylene, substituted ethene, and 1,3-butadiene chains (compounds 2). Biological results clearly indicated the unsubstituted ethene chain as the best structural motif to get the highest HDAC inhibitory activity, the sole exception to this rule being the introduction of the 1,3-butadienyl moiety into the 1a chemical structure (IC50(2f) = 0.77 microM; IC50(1a) = 3.8 microM). IC50 values of compounds 3, prepared as 1b homologues, revealed that between benzene and carbonyl groups at the pyrrole-C(4) position a hydrocarbon spacer length ranging from two to five methylenes is well accepted by the APHA template, being that 3a (two methylenes) and 3d (five methylenes) are more potent (2.3- and 1.4-fold, respectively) than 1b, while the introduction of a higher number of methylene units (see 3e,f) decreased the inhibitory activities of the derivatives. Particularly, 3a (IC50 = 0.043 microM) showed the same potency as SAHA in inhibiting HD2 in vitro, and it was 3000- and 2.6-fold more potent than sodium valproate and HC-toxin and was 4.3- and 6-fold less potent than trapoxin and TSA, respectively. Finally, conformationally constrained forms of 1b,c (compounds 4), prepared with the aim to obtain some information potentially useful for a future 3D-QSAR study, showed the same (4a,b) or higher (4c,d) HD2 inhibiting activities in comparison with those of the reference drugs. Molecular modeling and docking calculations on the designed compounds performed in parallel with the chemistry work fully supported the synthetic effort and gave insights into the binding mode of the more flexible APHA derivatives (i.e., 3a). Despite the difference of potency between 1b and 3a in the enzyme assay, the two APHA derivatives showed similar antiproliferative and cytodifferentiating activities in vivo on Friends MEL cells, being that 3a is more potent than 1b in the differentiation assay only at the highest tested dose (48 microM).     

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.     

Synthesis and antitumor activity of 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido[4,3-b]benzo[e]- and -benzo[g])indoles. A new class of antineoplastic agents

The thermal Fischer indolization of hydrazones resulting from 4-hydrazino-5-methyl-1H-pyridin-2-one and various beta- and alpha-tetralones led to 4-methyl-6,7-dihydro-2H,5H-pyrido[4,3- b]benzo[e]indol-1-ones and 4-methyl-11-dihydro-2H,5H-pyrido[4,3- b]benzo[g]indol-1-ones, respectively. After aromatization, these compounds were transformed by phosphorus oxychloride, giving 1-chloro-4-methyl-5H-pyrido[4,3- b]benzo[e]- and -benzo[g]indoles which were substituted by [(dialkylamino)alkyl]amines. The resulting 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido- [4,3-b]benzo[e]- and -benzo[g]indoles, as well as hydroxy derivatives obtained by demethylation of methoxylated compounds with hydrobromic acid, were tested for antitumor activity in vitro (leukemic and solid tumor cells) and in vivo on various experimental tumor models using the standard NCI protocols. 1-[[3-(Dialkylamino)propyl]-amino]-4-methyl-9-hydroxy-5H-pyrido[4,3- b]benzo[e]indoles appeared as a promising new class of antineoplastic agents.     

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: a new class of potent and selective 5-HT(1A) receptor ligands as conformationally constrained analogues of 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-arylpiperazines.

The present paper concerns the influence of conformational parameters on the recognition by rat 5-HT1A receptors of derivatives 4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1-(2-pyridinyl)piperazine (1a) and 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-[2-(2-pyridyloxy)ethyl]propanamine (3b), two highly potent and selective 5-HT1A receptor ligands. Fifteen corresponding flexible and rigid analogues were prepared following several synthetic routes and were tested in binding assays with radioligands at 5-HT1A, D2, and alpha1 receptors from rat brain membranes. Among the new derivatives emerged trans-4-[4-(3-methoxyphenyl)cyclohexyl]-1-(2-pyridinyl)piperazine (trans-8a) and trans-N-[4-(3-methoxyphenyl)cyclohexyl]-2-(2-pyridyloxy)ethylamine (trans-8b). These compounds can be considered as conformationally constrained analogues of compounds 1a and 3a, respectively. In fact, compounds trans-8a and trans-8b showed a marked enhancement in 5-HT1A receptor affinity when compared to the corresponding cis isomers. Because compound trans-8a was a potent and selective 5-HT1A ligand (K(i), nM: 5-HT1A = 0.028, D2 = 2194, alpha1 = 767), it was chosen as a lead to prepare other analogues that were tested at 5-HT1A, D2, and alpha1 receptors from rat brain membranes, showing high affinity at the 5-HT1A and selectivity vs D2 and alpha1 receptors. Selected compounds were tested for their affinity at the human cloned 5-HT1A, alpha1a, alpha1b, alpha1d receptor subtypes. They were also submitted to the [35S]GTPgammaS binding assay stimulating the 5-HT1A receptor-mediated G-protein activation, therefore behaving as full or as partial agonists. Finally, the ability of iv administration of trans-8a to induce fore-paw treading in rats was evaluated in comparison with 8-OH-DPAT. Although the affinity (K(i)) and in vitro activity (pD'2) of trans-8a at the 5-HT1A receptor were higher than those of 8-OH-DPAT, the compound was less potent than the reference standard in inducing the symptom.     

Synthesis of Several Substituted Phenylpiperazines Behaving as Mixed D2/5HT1A Ligands

Twenty-two different compounds have been synthesized with the aim of creating new, mixed D₂/5HT_1A ligands. For this purpose 1-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2-thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure-affinity requirements of 1-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D₁ and D₂) and 5-HT_1A receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [³H]SCH 23390 (D₁ selective), [³H]spiperone (D₂ selective) and 8-OH-[³H]DPAT (5-HT_1A selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D₁ dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[³H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [³H]spiperone-binding assay. The other compounds tested showed fair ( 1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c ) to high ( 1a, 1d, 2a, 1d, 3a, 3d–3f, 4a , and 4d ) affinity in the [³H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]-1-(2-methoxyphenyl)piperazine, 3a (K_i = 1.7 nm ). In the 8-OH-[³H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c–3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT_1A receptors (K_i = 2.6 nm ). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D₂ and 5-HT_1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.     

Synthesis and pharmacological investigations of some 4-hydroxycoumarin derivatives

The synthesis of ten coumarin derivatives of 4-hydroxycoumarin and various unsaturated ketones and aldehydes is described. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR, and mass-spectral data. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effects of the derivatives with respect to warfarin, showed that the compounds have anticoagulant activity. Compounds 4-hydroxy-3-[1-phenyl-2-(4'-chlorobenzoyl)ethyl]-2H-1-benzopyran-2-one 2b, 4-hydroxy-3-[1-(4-fluorophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one 3a, and 3, 3'-p-bromobenzylidene-bis-(4-hydroxy-2H-1-benzopyran-2-one) 4b showed slight acute toxicity and a greater anticoagulant effect than warfarin.     

2-[5-取代苯并咪(噻)唑-2-硫基]-1-(4-取代苯基)乙酮缩氨基胍的合成及NHE1抑制活性

目的设计合成缩氨基胍类化合物并研究其NHE1抑制活性。方法以4-取代苯乙酮(1)为原料,经溴代得α-溴代物(2),再与2-巯基-5-取代苯并咪(噻)唑(3)反应得到2-(5-取代苯并咪(噻)唑-2-硫基)-1-(4-取代苯基)乙酮(4),最后与氨基胍缩合得到目标化合物;以血小板肿胀模型进行初步的体外NHE1抑制活性筛选。结果与结论合成了12个新化合物,其结构经IR、1H-NMR及MS确证。初步的药理试验表明,12个目标化合物均有一定的NHE1抑制活性,其中化合物5b和5h的活性明显优于阳性对照药卡立泊来德。     

Synthesis of 1-(4-pyridyl)-2-amino-alkanoles

Synthesis of 1-(4-Pyridyl)-2-amino-alkanols The preparation of N-substituted derivatives of 1-(4-pyridyl)-2-amino-alkanols is described. In a preliminary pharmacological screening the compounds 3c, 3d, 3e, 3f showed β-receptor-blocking activity.     

N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity

N-(3-fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, >1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold (e.g., D3R K(i) for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 14. Mitt. 4-Oxo-4H-[1]benzofuro[3,2-b]pyrane und 4-Oxo-4H[1]benzothieno-[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XIV: 4-Oxo-4H-[1]benzofuro[3,2-b]pyranes and 4-Oxo-4H-[1]benzothieno[3,2-b]pyranes The 1,3-dicarbonyl compounds 1 condense with dialkyl oxalates to form the 1,3,5,6-tetracarbonyl compounds 2 , which hydrolize under mildly alkaline conditions to give the ketocarboxylic acids 3 . Compounds 2 and 3 cyclize on heating with alcohols, saturated with HCl, to yield the alkyl 4-pyrone-2-carboxylates 4 . The acids 5 , obtained from 4 , decarboxylate on heating with quinoline/copper to give the heterocycles 6 . Compound 6b is also obtained from 1b by reaction with N,N-dimethylformamide dimethyl acetal (DMFDMA) and treatment with acid of the product 8b , whereas 1a and DMFDMA give the derivative 7a . Compounds 4 were characterized in the form of their amides 10 . The pyrylium salts 11 were obtained from 6 by reaction with dimethyl sulfate/HClO₄. Compounds 4 and 6 are converted to the thiocarbonyl compounds 12 and 13 by reaction with P₄S₁₀. Condensation of 2 with triethyl orthoformate/acetic anhydride yields the alkyl 4-pyrone-3-ketocarboxylates 14 . Compound 15b , formed by hydrolysis from 14b, afforded the 4-pyrone-3-carboxylic acid 16b by oxidative decarbonylation.     

Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives

Synthesis of some new derivatives of 2-aryl-4-oxo-1-(4-quinazolyl)quinazolines is described. Methyl N-(4-quinazolyl)anthranilate was allowed to react with phenyl iso(thio)cyanate to give 3-phenyl-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydro-2, 4-dioxo- and 4-oxo-2-thioxoquinazolines (3a and 3b respectively) Alternatively, anthranilic acid amide derivatives were subjected to cyclization with aromatic aldehydes to give 2-aryl-4-oxo-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydroquinazolines 5. On the other hand, 2-chloro-4-(4-substituted 1-piperazinyl)quinazoline derivatives were subjected to the same type of reactions at the 2-position to afford the corresponding quinazoline derivatives 8 and 10 respectively. Furthermore, the acid amide 4b cyclized with acid chlorides to give the corresponding 2-aryl-1-(2-chloro-4-quinazolyl)-4-oxo-1, 4-dihydroquinazolines 11 from which the triazoloquinazoline derivatives 13 and 15 were synthesized through the intermediate hydrazine derivatives 12. Most of the newly synthesized compounds were tested for their antiinflammatory activities. However, some of the novel compounds were found to exhibit good antiinflammatory potencies.     

Bicyclische α-Aminosäuren, 4. Mitt.1) Synthese von 3-(1-Tetralyl)- und 3-[5-(5,6,7,8-Tetrahydro)-chinolyl]-alanin

Bicyclic α-Amino Acids, IV: Synthesis of 3-(L1,2,3,4-Tetrahydro-l-naphthalenyl)- and 3-(5,6,7,8-Tetrahydro-5-quinolinyl)alanine The title compounds 1a , b are prepared by Strecker synthesis with the aldehydes 7a , b which are available from 2a , b . The structures of 1a , b and the configurations of the isomeric nitriles 3a , b / 4a , b were elucidated by ¹H- and ¹³C-NMR spectroscopy.     

Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues

A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition.     

Importance of sulfonylimidazolidinone motif of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicity: Synthesis of 2-benzoyl-4-phenyl[1,2,5]thiazolidine-1,1-dioxides and their cytotoxcity

For probing the importance of planarity of imidazolidinone motif of 4-phenyl-1-(benzenesulfonyl)imidazolidinones 1 for their cytotoxicity, 4-phenyl-2-(benzoyl)[1,2,5]thiadiazolidine-1,1-dioxide (2a), 4-phenyl-2-(p-toluoyl)[1,2,5]thiadiazolidine-1,1-dioxide (2b), 4-phenyl-2-(phenylcarbamoyl)[1,2,5]thiadiazolidine-1,1-dioxide (3a), and 4-phenyl-2-(p-tolylcarbamoyl)[1,2,5]thiadiazolidine-1,1-dioxide (3b) were prepared along with their regioisomers (5a, 5b, 9a, 9b) and their cytotoxicity were measured against human lung carcinoma (A549), human colon carcinoma (COL0205), human ovarian cancer (SK-OV-3), human leukemic cancer (K562), and murine colon adenocarcinoma (Colon26) cell lines in vitro. All compounds prepared do not show any activity against all five cancer cell lines unlike 1. Compounds 1 possess planarity of imidazolidinone, especially in sulfonylurea moiety (-SO2NHCONH-). However compounds 2 and 3 have nonplanar 5-membered ring, [1,2,5]thiadiazolidine-1,1-dioxides. Such structural differentiation might result in the loss of activity. Therefore the inactivity of 2 and 3 could also be an indication for the necessity of planarity of imidazolidinone ring of 1 for their cytotoxic activity.     

Synthesis of pyranoid analogues of the anti-HIV active 3'-deoxy-2',3'-didehydrothymidine (D4T).

The primary hydroxy group of ethyl 2,3-dideoxy-alpha-D-erythro-hex-2-enopyranoside (1) was selectively protected and the secondary hydroxy group was deoxygenated via the dithiocarbonate 3 from which ethyl 6-O-(4-methoxybenzoyl)-2,3,4-trideoxy-alpha-D-glycero-hex-2-eno pyranoside (4) and its regioisomer (5) were produced. These were converted into didehydro nucleosides by glycosylation of silylated heterocyclic bases in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst. The configurations of the anomeric products were assigned by 1H-NMR analysis of the corresponding saturated compounds which were obtained by hydrogenation of the double bond in the carbohydrate moiety. The compounds 9a,b,d, 10a,b, 14a,b,e,f, and 15a,b,e,f did not show any significant activity against HIV or HSV-1.     

Hypobetalipoproteinemic agents. 2. Compounds related to 4-(1-adamantyloxy)aniline.

While the previously used displacement reaction of sodim 1-adamantyl oxide on 4-fluoronitrobenzene was applicable to the preparation of 4-(1-adamantyloxy)aniline and several related compounds, certain derivatives were not easily accessible by this route. Thus the recently reported ortho alkylation of anilines and the dicyclohexylcarbodiimide-promoted coupling of 1-adamantanol with phenols were useful in the preparation of aromatic-substituted derivatives. Furthermore, addition of phenylmagnesium bromide to 1-cyanoadamantane provided entry to the 4-(1-adamantylmethyl)aniline series. 4-(1-Adamantyloxy)aniline (3) is herein reported to be a more potent hypobetalipoproteinemic agent than the previously reported bicyclooctyloxy analogue. Replacement of the oxygen atom of 3 with sulfur (74) or methylene (62), but not nitrogen (71), results in active compounds. In the oxygen series derived from 3, the widest scope of substitution on nitrogen resulting in activity is found. The N-ethoxycarbonyl (5), acetyl (6), methyl (12), ethyl (13), N-methyl-N-(2-hydroxyethyl) (19), N-methyl-N-formyl (22), N,N-dimethyl (26), pyrrolidine (14), and piperidine (15) derivatives are active. Aromatic ring substitution also provided the active 3-chloro (44b), 2-fluoro (41b, 42, and 43), and 2-methylthiomethyl (48) compounds. Thus these active compounds are identified for further development as hypobetalipoproteinemic agents.