Antiviral activity of some beta-diketones. 3. Aryl bis(beta-diketones). Antiherpetic activity.

A series of bis(beta-diketones) was synthesized and tested in vitro for antiviral actitity against herpes simplex type 2. Two parameters which were studied in an effort to optimize activity were the nature of the aryl group and the length of the alkyl bridge. One of the more active compounds, 4,4'-[(1,4-phenylenedioxy)bis(6,1-hexanediyl)]-bis[3,5-heptanedione] (6), was evaluated more extensively and found to inhibit the cytopathic effect in tissue culture of herpes simplex virus type 1 as well as type 2. Compound 6 was evaluated in vivo topically against herpes simplex type 1 in experimentally induced skin infections in guinea pigs. A topical treatment with 2% of 6 in a vanishing cream base, administered 24 h postinfection applied five times daily for 4 days, significantly reduced the number and size of herpetic vesicles.     

Antiviral activity of some beta-diketones. 1. Aryl alkyl diketones. In vitro activity against both RNA and DNA viruses.

The discovery that 4-[3-ethyl-6-[(3,4-methylenedioxy)phenyl]-3-hexenyl]-3,5-heptanedione (40) exhibited an in vitro inhibitory effect against equine rhinovirus led to a structure--activity study to establish the criteria for optimum activity. Modification of the bridge included removal of the ethyl group and reduction of the double bond. The heptanedione was replaced with hexanedione and pentanedione with a minimal effect. The effect of replacing the heptanedione with beta-keto esters and monoketones was also investigated. Maintaining the hexamethylene bridge and heptanedione, the methylenedioxy group was replaced with various substitutents. In general, most substituents did not adversely affect activity particularly against equine rhinovirus although there was some variation in activity against herpesvirus. Strongly hydrophilic groups significantly reduced activity. Finally, the effect of varying the length of the alkyl bridge was examined in the 4-hydroxyphenyl series, where peak activity was attained with n = 8.     

Synthesis and antibacterial activity of substituted oxotriazolylphenyl oxazolidinones

A series of 3-(4'-(2'-alkyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-substituted oxazolidinones was designed and synthesized for in vitro antibacterial activity testing against fourteen Gram-negative and six Gram-positive standard organisms. The minimum inhibitory concentration (MIC) was determined by agar dilution at concentrations of 0.10, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25 microg/mL. Different alkyl groups at the 2'-position played an important role in the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinone was active against Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus enteridis and Streptococcus nonhemolyticus, whereas 2'-methyl, 2'-propyl and 2'-n-butyl counterparts did not show activity at 6.25 microg/mL. Modification of the 5-substitutent of oxazolidinones also affected the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinones was approximately two fold more potent than 5-chloroacetamido, 5-dichloroacetamido and 5-trifluoroacetamido counterparts against Streptococcus enteridis. None of these compounds showed growth inhibition against fourteen Gram-negative organisms at 6.25 microg/mL.     

Biological activity of alkyl 2-(acylthio)benzoates

Of a series of synthetic alkyl 2-(acylthio)benzoate (1-20), all the derivatives except for n-butyl 2-butyrylthiobenzoate (18) and n-butyl 2-n-valerylthiobenzoate (20) showed clear phytogrowth-inhibitory activity. All the compounds tested except for methyl 2-butyrylthiobenzoate (3) exhibited cytotoxic activity on mouse splenic T cells. Strong phytogrowth-inhibition and cytotoxic activity were found with 1, 6, 11 and 16 with an acetylthio group at C-2, suggesting that the acetyl group seems to play an important role in both activities of alkyl 2-(acylthio)benzoates. Among them, methyl 2-acetylthiobenzoate (1) was the strongest inhibitor. On the other hand, potent inhibition of prolyl endopeptidase was exhibited by 2, 7, 12 and 17 with a propionylthio group at C-2. These findings imply that a propionyl group might be useful for increasing the inhibitory activity against on prolyl endopeptidase.     

Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 2. Structure-activity relationships of thiazolidinone derivatives.

CP-060 (1), 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3, 4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-on e, is a novel type of Ca(2+) antagonist possessing both Ca(2+) overload inhibition and antioxidant activity. The structure-activity relationships for this series of compounds were studied by synthesizing the analogues and evaluating these three kinds of activity. Ca(2+) antagonistic activity was largely determined by the lipophilicity of the phenyl group at the 2-position and the length of the alkyl chains. As for the antioxidant activity, it was demonstrated that the phenolic hydroxyl group is an essential structural element. Compounds with potent activity were evaluated for their effect on the coronary blood flow in vivo. Among these compounds, compound 1 was shown to be the most potent. Furthermore, the enantiomers of 1 were resolved by high-performance liquid chromatography with a chiral column. Compound (-)-1 showed about 10 times higher Ca(2+) antagonistic activity than (+)-1, though both enantiomers had similar potency in Ca(2+) overload inhibition and antioxidant activity. An X-ray crystal structure determination of (-)-1 hydrogen fumarate identified (-)-1 as having S configuration at the 2-position.     

Relation between structure and antimicrobial activity of 2-(N,N,N-trialkylammonio)alkyl hydrogen phosphates

A series of phosphobetaines [2-(N,N,N-trialkylammonio)alkyl hydrogen phosphates], having different alkyl chains and a methylene bridge separating the phosphate and ammonio group, was investigated in order to provide a new antimicrobial agent. Maximal activity was obtained with the compound having a hexadecyl group as a long-chained alkyl group, two methyl groups as short-chained alkyl groups, and a dimethylene bridge as an intercharge distance. In contrast, sodium 2-(N-hexadecyl-N-methylamino)ethyl hydrogen phosphate, 2-(N-hexadecyl-N,N-dimethylammonio)-1-hydroxyethyl iodide, and N-octadecyl-N,N-dimethylammonio acetate showed decreased activity, indicating that the presence of a phosphobetaine moiety was essential for activity. Thus, 2-(N-hexadecyl-N,N-dimethylammonio)ethyl hydrogen phosphate has been found to possess strong antimicrobial activity and a broad antimicrobial spectrum against nine kinds of bacteria (e.g., fungi, yeast, gram-negative and gram-positive bacteria), which are comparable with those of chlorhexidine digluconate.     

Potential antitumor agents. 50. In vivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide

The synthesis, physicochemical properties, and antitumor activity of a series of N-[2-(dialkylamino)alkyl]-acridine-4-carboxamides are reported. The compounds bind to DNA by intercalation, but exist under physiological conditions as monocations due to the weakly basic acridine chromophore (pKa = 3.5-4.5). The acridine-4-carboxamides show very broad structure-activity relationships (SAR) for antileukemic activity, with substituents at nearly all acridine positions proving acceptable. The compounds also show remarkable activity against the Lewis lung solid tumor in vivo, with several analogues capable of effecting 100% cures of the advanced disease. The broad SAR and high solid-tumor activity of the 9-acridine-4-carboxamides imply they should be considered as a completely new class of antitumor agent.     

New alpha-amino phosphonic acid derivatives of vinblastine: chemistry and antitumor activity

A series of new amino phosphonic acid derivatives of vinblastine (1, VLB) has been synthesized and tested in vitro and in vivo for antitumor activity. The compounds were obtained from O4-deacetyl-VLB azide. All of the new products studied were capable of inhibiting tubulin polymerization in vitro. The most potent antitumor compounds bore an alkyl substituent on the phosphonate. In these compounds, the anti-tumor activity strongly depended on the stereochemistry of the phosphonate. The phosphonate (1S)-[1-[( O4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastin-3-yl] carbonyl]amino]-2-methylpropyl]phosphonic acid diethyl ester exhibited a remarkable activity against cancer cell lines both in vitro and in vivo.     

Studies on the antibacterial action of novel gem-diphenyl-spiro-cyclopropano- oxazolones and 2-aryl(alkyl)-4-ylidene-oxazol-5-ones.

The preparation and in vitro antibacterial activity of a novel series of gem-diphenyl-spiro-cyclopropano-oxazolones (cis-1,2,2,5-tetraphenyl 6-oxa-4-azaspiro[2.4]hept-4-en-7-one) are described. The overall activity of these compounds was higher than that of the 2-aryl(alkyl)4-ylidene-oxazol-5-ones (azlactones). The gem-diphenyl-spiro-cyclopropano-oxazolones 1-4 have emerged as the most potent derivatives when tested against bacteria.     

Synthesis and antihypertensive activity of 3-[(substituted-carbonyl)amino]-2H-1-benzopyrans.

The synthesis and antihypertensive activity of a series of novel 3-[(substituted-carbonyl)amino]-2H-1-benzopyran-4-ols, administered orally to spontaneously hypertensive rats, are described. Optimum activity in this series was observed for compounds with branched alkyl or branched alkylamino groups flanking the carbonyl or thiocarbonyl group (21, 31-33), which were approximately equipotent to cromakalim. Replacement of the 4-hydroxyl group by hydrogen, methoxy, or amino in this series only led to a slight reduction in potency. These observations are in marked contrast to the structure-activity relationships previously found for the 4-amidobenzopyran-3-ols. The antihypertensive activity of representative compounds 15 and 33 was attempted by preatreatment with glibenclamide, and thus these compounds may belong to the series of drugs which have been classified as potassium channel activators.     

N-phenylpiperazine derivatives with hypocholesterolemic activity

A series of new 4-(4-phenyl-1-piperazinyl)-1-(4-fluorophenyl)-2-(acyloxy)-1-butanones and 4-aryl-5-[omega-(4-aryl-1-piperazinyl)alkyl]-1,3-dioxol-2-ones were synthesized and tested preliminarily for hypolipemic activity. Plasma cholesterol-lowering activity in normal rats was found especially in several dioxolones, two of the most active compounds (6 and 8) being more potent than clofibrate. 4-(4-Chlorophenyl)-5-[2-(4-phenyl-1-piperazinyl)ethyl]-1,3-dioxol- 2-one (8, LR-19,731) has been selected for clinical trials.     

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.     

Synthesis,SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity

We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF(3), 4-OCF(3), 4-SO(2)Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, (n)()Pr, (i)()Pr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.     

Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity

Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6). The introduction of an alkyl, alkoxyalkyl, or acyloxyalkyl ester group to the molecule resulted in an increase of antiviral activity; the most active compound was found to be the hexadecyloxyethyl ester 5. The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.     

Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 1. Hydrazines

The synthesis and anticonvulsant activity of a series of 2-aryl-5-hydrazino-1,3,4-thiadiazoles are described. The combination of preferred aromatic substituents in the 2-position coupled with alkyl substitution on the hydrazine moiety led to a number of potent compounds lacking sedation, ataxia, or lethality. 5-(2-Biphenylyl)-2-(1-methylhydrazino)-1,3,4-thiadiazole (4m) represents a new class of anticonvulsant agent and compares favorably with the standard drugs phenytoin, phenobarbital, and carbamazepine.     

5-Piperazinylalkyl-2(3H)-oxazolones with neuroleptic activity

A series of new 4-aryl-5-[omega-(4-aryl-1-piperazinyl)alkyl]-2(3H)- oxazolones was synthesized and tested for neuroleptic activity in mice and rats. Several compounds exhibited interesting neuroleptic activity with very low liability to the extrapyramidal side effects. In particular the activity of 4-(4-fluorophenyl)-5-[2-[4-(3,5-dichlorophenyl)-1- piperazinyl]ethyl]-2(3H)-oxazolone (14) was greater than that of butropipazone and fluanisone, while of the same order of that of chlorpromazine; however, the product showed a longer lasting activity and minor ability to produce catalepsy as compared with the reference drugs.     

Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group

For the purpose of screening of inhibitors that are effective for wide range of metallo-beta-lactamases, the inhibitory effect of two series of compounds, 2-omega-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1-4)) and N-[(7-chloro-quinolin-4-ylamino)-alkyl]-3-mercapto-propionamide (QuinolineCnSH (n=2-6)), where n denotes the alkyl chain length, on metallo-beta-lactamases IMP-1 and VIM-2 was examined. These inhibitors contain a thiol group and a hydrophobic group linked by variable-length methylene chain. PhenylCnSH (n=1-4) was found to be a potent inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both IMP-1 (IC(50)=1.2 microM) and VIM-2 (IC(50)=1.1 microM) among this study. When the number of methylene units was varied, QuinolineC4SH showed the maximum inhibitory activity against IMP-1 and VIM-2 (IC(50)=2.5 microM and IC(50)=2.4 microM). The relationship between the inhibitory effect of the alkyl chain length was different for both series of inhibitors, suggesting that IMP-1 has a tighter binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent for metallo-beta-lactamases.     

Synthesis and antihypertensive activity of 4-(substituted-carbonylamino)-2H-1-benzopyrans

The synthesis and antihypertensive activity of a series of novel 4-(substituted-carbonylamino)-2H-1-benzopyran-3-ols, administered orally to conscious spontaneously hypertensive rats, are described. Optimum activity was observed for compounds with alkyl, amino, or aryl groups flanking the carbonyl group. Of the alkyl and amino series the most potent compounds contained the methyl and methylamino groups, respectively. Several analogues have been compared with cromakalim (1) for their effects on potassium ion efflux in the rabbit mesenteric artery using rubidium-86 as a marker. The ability of each compound to enhance rubidium-86 efflux is approximately parallelled by its blood pressure lowering activity, and thus these analogues, like compound (1), belong to the series of drugs which have been classified as potassium-channel activators.     

Synthesis and antimicrobial activity of new diazoimidazole derivatives containing an N-acylpyrrolidine ring.

A series of 4-diazoimidazole-5-carboxamides bearing in position 2 lipophilic substituents was synthesized and their antimicrobial activity was evaluated in vitro against pathogenic Gram-positive, Gram-negative bacteria and fungi. Some compounds presented antifungal activity, particularly two derivatives (1g and 1h) showed good MIC values (10-50 microg/ml) against both moulds and yeasts.