Showing papers in "Journal of Medicinal Chemistry in 1977"
TL;DR: Swain and Lupton's gamma and kappa values have been calculated from the omego constants for pi and omega for a miscellaneous group of aromatic substituents of interest to medicinal chemists.
Abstract: Constants for pi and omega ahve been measured for a miscellaneous group of aromatic substituents of interest to medicinal chemists. Swain and Lupton's gamma and kappa values have been calculated from the omego constants. Values for molar refractivity are also given for each of the substituents.
384Â citations
TL;DR: The use of distribution coefficients (log D) for the analysis of structure-activity relationships of ionizable compounds is described, with the advantage that the influence of pKa or equivalent electronic factors on distribution can be distinguished from electronic effects related to mechanism of action.
Abstract: The use of distribution coefficients (log D) for the analysis of structure-activity relationships of ionizable compounds is described. (D is the ratio of the equilibrium concentration of compound in an organic phase to the total concentration of un-ionized and ionized species in the aqueous phase at a given pH.) Simpler equations, often with improved correlations, have resulted. This method has the advantage that the influence of pKa or equivalent electronic factors on distribution can be distinguished from electronic effects related to mechanism of action. Several absorption studies are reanalyzed as well as studies on membrane conductance and uncoupling of oxidative phosphorylation.
218Â citations
TL;DR: It was concluded that the benzyl triesters of cAMP are useful derivatives which can be efficiently and specifically converted to the parent nucleotide.
Abstract: A series of triesters of adenosine cyclic 3',5'-phosphate was synthesized by treatment of the free acid with various diazoalkanes (R=H, CH3, C6H5,0-NO2C6H4, p-NO2C6H4, p-CH3C6H4). The resulting diastereomeric mixtures were separated into their axial and equatorial components. Hydrolysis of the compounds was examined as well as photolysis of the photolabile o-nitrobenzyl ester. All compounds were then tested for their ability to activate the cAMP-dependent protein kinase and for their ability to serve as a substrate for the cAMP phosphodiesterase showing almost no effect on either enzyme. In a biological assay the benzyl triesters were able to penetrate into C 6 rat glioma cells and to induce the typical morphological alteration of the cell shape known for high cellular levels of cAMP. It was concluded that the benzyl triesters of cAMP are useful derivatives which can be efficiently and specifically converted to the parent nucleotide. Benzyl derivatives of biologically active phosphodiesters may provide a useful tool for study in biology and pharmacology.
211Â citations
TL;DR: A procedure is described in which an initial small group of compounds is selected, tested, and ordered according to potency, then compared to the tabulated potency order calculated for various parameter dependencies relating to hydrophobic, electronic, and steric effects.
Abstract: A procedure is described in which an initial small group of compounds is selected, tested, and ordered according to potency. The potency order in the group is then compared to the tabulated potency order calculated for various parameter dependencies relating to hydrophobic, electronic, and steric effects. From this activity pattern analysis the probable operative parameters can be deduced and a new substituent selection made for the synthesis of potentially more potent analogues. Application of the method is illustrated with a series of examples. It differs from a previously described decision tree, single compound stepwise approach in that it involves the batchwise analysis of small groups of compounds, usually the preferred procedure for logistical reasons if the compounds are relatively easy to synthesize.
204Â citations
TL;DR: The bilinear model explains the particular effect that in homologous series the relationship between biological activity and hydrophobic character is strictly linear for the lower members, while for higher members this relationship is nonlinear.
Abstract: The bilinear model, log 1/C =a log P-b log (betaP+1) +C, a new model for nonlinear dependence of biological activity on hydrophobic character, is applied to 57 data sets of biological activity values in homologous series. From a comparison of the statistical parameters and the residuals obtained with the bilinear model and the parabolic model, the superiority of the bilinear model for a precise quantitative description of both linear and nonlinear parts of sturcture-activity relationships can be derived; the bilinear model explains the particular effect that in homologous series the relationship between biological activity and hydrophobic character is strictly linear for the lower members, while for higher members this relationship is nonlinear.
190Â citations
TL;DR: Thiazole nucleosides were tested for in vitro activity against type 1 herpes virus, type 3 parainfluenza virus, and type 13 rhinovirus and they were evaluated as potential inhibitors of purine nucleotide biosynthesis.
Abstract: A general reaction of glycosyl cyanides with liquid hydrogen sulfide in the presence of 4-dimethylaminopyridine to provide the corresponding glycosylthiocarboxamides is described. These glycosylthiocarboxamides were utilized as the precursors for the synthesis of 2-D-ribofuranosylthiazole-4-carboxamide and 2-beta-D-ribofuranosylthiazole-5-carboxamide (23). The structural modification of 2-beta-D-ribofuranosylthiazole-4-carboxamide (12) into 2-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)thiazole-4-carboxamide (15), 2-beta-D-ribofuranosylthiazole-4-thiocarboxamide (17), and 2-(5-deoxy-beta-D-ribofuranosyl)thiazole-4-carboxamide (19) is also described. These thiazole nucleosides were tested for in vitro activity against type 1 herpes virus, type 3 parainfluenza virus, and type 13 rhinovirus and an in vivo experiment was run against parainfluenza virus. They were also evaluated as potential inhibitors of purine nucleotide biosynthesis. It was shown that the compounds (12 and 15) which possessed the most significant antiviral activity were also active inhibitors (40-70%) of guanine nucleotide biosynthesis.
176Â citations
TL;DR: In a series of compounds in which the L-leucine residue of bestatin was substituted with other amino acids, only the one containing isoleucine showed more activity than bestatin, and the p-Methyl-, p-chloro-, and p-nitrobestatins showed greater activity.
Abstract: Stereoisomers and analogues of bestatin, [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, were synthesized and tested for aminopeptidase B and leucine aminopeptidase inhibiting activity. Among the eight stereoisomers, the 2S stereoisomers exhibited strong activity. In a series of compounds in which the L-leucine residue of bestatin was substituted with other amino acids, only the one containing isoleucine showed more activity than bestatin. Norleucine, norvaline, methionine, valine, serine, glutamine, phenylalanine, glutamic acid, proline, and lysine analogues gave, in that order, decreasing activity. Alkyl and phenyl sub stitution for the benzyl group of bestatin decreased the activity markedly. p-Methyl-, p-chloro-, and p-nitrobestatins showed greater activity than bestatin.
171Â citations
TL;DR: The solid-phase synthesis of human beta-endorphin is described, and the synthetic beta h- endorphin possesses antinociceptive properties as estimated by the tail-flick, hot-plate, and writhing tests in mice.
Abstract: The solid-phase synthesis of human beta-endorphin is described. A yield of 32% is achieved based on starting resin. The synthetic product behaves as a homogeneous peptide in partition chromatography, paper electrophoresis, thin-layer chromatography, disc electrophoresis, amino acid composition, and a tryptic map. The synthetic beta h-endorphin possesses antinociceptive properties as estimated by the tail-flick, hot-plate, and writhing tests in mice. When applied centrally, beta h-endorphin is 17-48 times more potent than morphine. It is 3.4 times more potent than morphine when injected intravenously. The analgesic responses are blocked by the specific opiate antagonist, naloxone.
158Â citations
TL;DR: Eighteen substituted 2,5-bis(4-guanylphenyl)furans and related analogues, including "masked" amidines in which the guanyl function is incorporated into a heterocyclic ring, have been synthesized and their antimalarial and antitrypanosomal activity has been evaluated.
Abstract: Eighteen substituted 2,5-bis(4-guanylphenyl)furans and related analogues, including "masked" amidines in which the guanyl function is incorporated into a heterocyclic ring, have been synthesized and their antimalarial and antitrypanosomal activity has been evaluated. None of the compounds exhibited high orders of antimalarial activity; however, 11 were very active against Trypanosoma rhodesiense in mice. Six compounds, including 2,5-bis(4-guanylphenyl)furan (4) and its 3-chloro (32), 3,4-dichloro (31), 3-methyl (25), 3,4-dimethyl (20), and 3-chloro-4-methyl (38) derivatives, produced cures in mice at submilligram dosage levels; the 3,4-dimethyl (20) analogue exhibited a prolonged curative effect providing protection for 30 days after a single dose against a challenge by T. rhodesiense. These six compounds are somewhat more active in this screen than stilbamidine, hydroxystilbamidine, and pentamidine. The "masked" amidines generally exhibited lower antitrypanosomal activity than their true guanyl counterparts. Compound 4 was synthesized from 1,4-di-p-bromophenyl-1,4-butanedione by cyclodehydrative furanization to 2,5-bis(4-bromophenyl)furan (2) which was allowed to react with Cu2(CN)2 to produce the corresponding bis-nitrile 3. The latter compound was ultimately converted by way of an imidate ester into 4. Similarly, the 3- and/or 4-substituted derivatives of 2 were employed to prepare the other members of the series.
155Â citations
TL;DR: In this paper, a correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4, and the pharmacological equivalence of these groups in H2-receptor antagonists is described.
Abstract: In the histamine H2-receptor antagonist metiamide (2a) isosteric replacement of thione sulfur (=S) by carbonyl oxygen (=O) or imino nitrogen (=NH) affords the urea 2c and guanidine 2d which are antagonists of decreased potency. The guanidine is very basic and at physiological pH is completely protonated. However, introduction of strongly electronegative substituents into the guanidine group reduces basicity and gives potent H2-receptor antagonists, viz. the cyanoguanidine 2b (cimetidine, "Tagamet") and nitroguanidine 2e. A correspondence between the activity of thioureas and cyanoguanidines is demonstrated for a series of structures 1-4. The close correspondence between cyanoguanidine and thiourea in many physicochemical properties and the pharmacological equivalence of these groups in H2-receptor antagonists leads to the description of cyanoguanidine and thiourea as bioisosteres. Acid hydrolysis of the cyanoguanidine 2b yields the carbamoylguanidine 2f at ambient temperatures and the guanidine 2d at elevated temperatures. Cimetidine is slightly more active than metiamide in vivo as an inhibitor of histamine-stimulated gastric acid secretion and has clinical use in the treatment of peptic ulcer and associated gastrointestinal disorders.
148Â citations
TL;DR: Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety alkylate the thiol group of reduced glutathione and L-cysteine in vitro, and it is thought that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen.
Abstract: Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.
TL;DR: Five compounds showed antiinflammatory activity and three possessed hypnotic properties and two of them had unknown properties.
Abstract: 5-Alkoxy-3-(N-substituted carbamoly)-1-phenylpyrazoles were prepared and tested for antiinflammatory and hypnotic activity. Four compounds showed antiinflammatory activity and three possessed hypnotic properties.
TL;DR: A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test and are of possible value for the treatment of asthma.
Abstract: A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test. These compounds are active when administered orally in rats and of possible value for the treatment of asthma.
TL;DR: The yield and simplicity of operation in this method are vastly superior to those previously reported for this transformation.
Abstract: Brief treatment of codeine (1) in chloroform with boron tribromide has consiste-tly given morphine (2) in 90-91% yield after a simple isolation procedure. The yield and simplicity of operation in this method are vastly superior to those previously reported for this transformation.
TL;DR: When the relative hydrogen-bonding effect of drugs on phases involved in the binding at the site of biological action differs from that in the 1-octanol-H2O partitioning phases used as the reference to estimate the hydrophobicity, a parameter (or parameters) which represents the "extra" hydrogen- bonding effect on the biological activity is required in the Hansch-type correlations.
Abstract: When the relative hydrogen-bonding effect of drugs on phases involved in the binding at the site of biological action differs from that in the 1-octanol-H2O partitioning phases used as the reference to estimate the hydrophobicity, a parameter (or parameters) which represents the "extra" hydrogen-bonding effect on the biological activity is required in the Hansch-type correlations. As a first approximation, the effect is analyzed in terms of the ratio of hydrogen-bonding association constants and the ratio of molarities of hydrogen-bonding species constituting the biological and organic phases. Sometimes, the association constants in both phases are so similar that they are not important in determining the extra hydrogen-bonding effect. The net result is that the effect is expressible by an indicator variable term the slope of which corresponds to the molarity ratio. The variable only applies to substituents having appreciable association capability in correlating a certain biological action exhibited by a series of congeners.
TL;DR: The model rationalizes the structure-activity relationships of enzyme substrates and inhibitors and appears to be in agreement with biochemical studies of the enzyme.
Abstract: Conformational analysis of indomethacin and other nonsteroidal antiinflammatory drugs leads to formulation of a hypothetical complementary receptor site model. The same model can serve to describe the prostaglandin cyclooxygenase active site, and, indeed, arachidonic and other polyunsaturated fatty acids could be folded on the model in a manner which rationalizes their stereospecific transformation to cyclic endo-peroxides (PGG). The model rationalizes the structure-activity relationships of enzyme substrates and inhibitors and appears to be in agreement with biochemical studies of the enzyme.
TL;DR: In this article, a series of neurotensin analogues in which each amino acid has been successively replaced by its D isomer, as well as analogues involving modifications at positions 3 and 11 and a cyclic compound [Cys2,13]-NT, has been synthesized by solid-phase methodology.
Abstract: A series of neurotensin (NT) analogues in which each amino acid has been successively replaced by its D isomer, as well as analogues involving modifications at positions 3 and 11 and a cyclic compound [Cys2,13]-NT, has been synthesized by solid-phase methodology. After purification by conventional techniques the compounds were characterized by thin-layer chromatography, amino acid analysis, and optical rotation. Further characterization of the analogues by high-pressure liquid chromatography demonstrates the high resolving power of this new method. Each analogue was studied for its ability to induce hypothermia in cold-exposed rate (4 degrees C) in vivo and to bind to mast cells in vitro. Although close correlation in potencies was not found for all the analogues tested in both assay systems, they substantiate the basic observation that substitutions in positions 1-9 produced active peptides whereas modification of residues 10-13 considerably decreased biological response in vitro and in vivo. One exception is the higher potency of [D-Phe11]-NT and [D-Tyr11]-NT in vivo. The differences between the efficacies of these analogues in vivo and in vitro are discussed.
TL;DR: Stereotypical behavioral effects produced by direct intracerebral administration of some of the agents were shown to differ strikingly from responses resulting from peripheral administration, and centrally mediated responses of hyperactivity and sterotypical gnawing-biting head and limb movements were showed to be separable in some test compounds.
Abstract: A series of variously N-substituted 2-aminotetralins having OH groups at 5 and 6 and at 6 and 7 positions, as well as nonoxygenated systems, has been evaluated for central dopaminergic effects. Stereotypical behavioral effects (sniffing, compulsive gnawing, and hyperactivity) produced by direct intracerebral administration of some of the agents were shown to differ strikingly from responses resulting from peripheral administration. The centrally mediated responses of hyperactivity and sterotypical gnawing-biting head and limb movements were shown to be separable in some test compounds. An improved route to 2-aminotetralin systems has been utilized for some of the compounds, which involves Pummerer rearrangement and cyclization of beta-keto sulfoxides and reductive amination of beta-tetralones with a NaBH4-carboxylic acid complex.
TL;DR: Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide, and comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents.
Abstract: Forty derivatives (1-40) of pyrazolo[1,5-a]pyrimidine were synthesized and evaluated for antianxiety properties via gross behavioral observations in rats. Five of these compounds, including 5,7-dimethylpyrazolo[1,5-a]pyrimidine (6) and the 3-fluoro (7), 3-chloro (8), 3-bromo (9), and 3-iodo (10) derivatives, were selected for advanced evaluation. Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide. Comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents. These compounds also lacked activity in anticonvulsant and analgesic tests. Acute toxicity data (mouse, ip and po) indicated that 8-10 had excellent therapeutic ratios, although 10 was more poorly absorbed than 8 and 9. Further demonstration of anxiolytic efficacy was obtained by comparing the effects of 8 and 9 with the benzodiazepines in modifying provoked aggression in monkeys, rats (muricide), and fighting mice. The most remarkable observation, however, was that 8 and 9 had no effect, at the anxiolytic threshold, in potentiating the CNS depressant effects of ethanol or sodium barbital (po) in treated mice. In contrast, diazepam and chlorodiazepoxide potentiated this drug interaction effect at minimal anxiolytic doses.
TL;DR: 5-(Tetradecyloxy)-2-furancarboxylic acid was found to lower blood lipids and to inhibit fatty acid synthesis with minimal effects on liver weight and liver fat content.
Abstract: 5-(Tetradecyloxy)-2-furancarboxylic acid (91, RMI 14514) was found to lower blood lipids and to inhibit fatty acid synthesis with minimal effects on liver weight and liver fat content. This fatty acid-like compound represents a new class of hypolipidemic agent; it is effective in rats and monkeys. The compound resulted from discovery of hypolipidemic activity in certain beta-keto esters, postulation and confirmation of the corresponding benzoic acids as active metabolites, and systematic exploration of the structure--activity relationships.
TL;DR: Two minor metabolites of prazosin, 2-(1-piperazinyl)-4-amino- 6,7-dimethoxyquinazoline and 2,4-diamino-6, 7-Dimethoxy Quinazoline, are also described, which are less potent blood pressure lowering agents in dogs than prazoin but may contribute to its antihypertensive effect.
Abstract: The 6-O-demethyl and 7-O-demethyl analogues of the new antihypertensive drug prazosin [2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride] have been unequivocally synthesized via separate ten-step reaction sequences starting from isovanillin and vanillin, respectively. The 6-O-demethyl derivative was found to be identical with the major prazosin metabolite formed in dog and rat, while the 7-O-demethyl derivative was identical with another, less prevalent but significant metabolite. Two minor metabolites of prazosin, 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline and 2,4-diamino-6,7-dimethoxyquinazoline, are also described. All four metabolites are less potent blood pressure lowering agents in dogs than prazosin but may contribute to its antihypertensive effect, since they account for a major portion of the administered dose.
TL;DR: Warfarin in solution is shown to consist of three interconverting tautomeric structures, two of which are cyclic diastereomeric hemiketals, while the third and minor component is the open-chain intermediate form.
Abstract: Warfarin in solution is shown to consist of three interconverting tautomeric structures, two of which are cyclic diastereomeric hemiketals, while the third and minor component is the open-chain intermediate form. The configurations of all the tautomers as well as the major conformations of the cyclic tautomers are assigned. The assignments are supported by comparison with the chemical shift and coupling constant parameters of structurally fixed model compounds.
TL;DR: Threonine substitution has brought about a substantial enhancement in oxytocic activity and a fivefold enhancement in O/A selectivity in these peptides, which might offer a greater margin of safety than oxytocin in those clinical stiuations in which the latter is currently employed.
Abstract: [4-Threonine, 7-glycine]oxytocin and [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin) were synthesized by a combination of solid-phase and classical methods of peptide synthesis. A protected octapeptide was synthesized by the solid-phase method and following ammonolysis and purification 1 + 8 couplings in solution were employed to furnish the required key nonapeptide and acyl octapeptide intermediates, respectively. [7-Glycine]oxytocin was prepared from a sample of the protected nonapeptide intermediate used in the original synthesis of this peptide. [7-Glycine]oxytocin has an oxytocic potency (O) of 93 +/- 4 units/mg and an antidiuretic potency (A) of 0.0056 +/- 0.0003 units/mg. It has an O/A ratio of 16 000. [4-Threonine, 7-glycine]oxytocin has an oxytocic potency of 166 +/- 4 units/mg and an antidiuretic potency of 0.002 +/- 0.0004 units/mg. Its O/A ratio is 83 000. Threonine substitution has thus brought about a substantial enhancement in oxytocic activity and a fivefold enhancement in O/A selectivity. Hydroxy [Thr4, Gly7]oxytocin has an oxytocic potency of 218 +/- 8 units/mg and antidiuretic potency of 0.0040 +/- 0.0005 units/mg. Its O/A ratio is thus 54 500. All three 7-glycine-substituted analogues exhibit a marked sensitivity to Mg2+ on the rat uterus assay ststem and in the presence of 0.5 mM Mg2+ had oxytocic potencies in the range of 900-1000 units/mg. Should these peptides exhibit enhanced oxytocic selectivity in humans, they might offer a greater margin of safety than oxytocin in those clinical stiuations in which the latter is currently employed.
TL;DR: Various classes of transient derivatives of L-Dopa have been synthesized, systematically protecting one or more of the main sites of metabolism in the molecule: the carboxy function, the amino, and/or the catechol system, resulting in a significantly better bioavailability of the drug.
Abstract: Various classes of transient derivatives of L-Dopa have been synthesized, systematically protecting one or more of the main sites of metabolism in the molecule: the carboxy function, the amino, and/or the catechol system. The derivatives studied include carboxy esters, phenol esters, amides, peptides, and various combinations of these functions. A number of these derivatives effectively prevent the metabolism of L-Dopa prior to and/or during the absorption process, resulting in a significantly better bioavailability of the drug. In vivo studies using dogs showed up to 2.5-fold increase in L-Dopa blood levels. The metabolism as well as toxicity aspects of the prodrugs is also discussed.
TL;DR: The results suggest that binding to the enzyme is primarily mediated by the pyrophosphate moiety assisted by relatively nonspecific lipophilic interactions, and decreasing the chain length and saturating double bonds severely reduces binding, while substitution at the 2,3, and 4 positions, and lengthening of the chain, is well tolerated.
Abstract: The pyrophosphates of the following farnesol analogues have been synthesized: 2-methylfarnesol; 7,11-dimethyl-3-ethyl-2,6,10-dodecatrien-1-ol; 3-demethylfarnesol; 4-methylthiofarnesol; 7,11-dimethyl-3-iodo-2,6,10-dodecatrien-1-ol; 7,11-dimethyl02-iodo-2,6,10-dodecatrien-1-ol; 7,11-dimethyldodeca-6,10-dien-2-yn-1-ol; phytol; 3,7,11-trimethyl-2-dodecen-1-ol; 3,7,11-trimethyldodecan-1-ol; and geraniol. The double bonds in all the above compounds were in the E configuration, except phytol, which was a 7:3 mixture of 2E and 2Z isomers. Each of the pyrophosphates inhibits the incorporation of labeled farnesyl pyrophosphate into squalene by a yeast enzyme preparation. Free alcohols and monophosphates are inactive. The analogues, listed in order of decreasing inhibitory strength, are, by kinetic analysis, competitive or mixed inhibitors. Irreversible inhibition is not observed. The results suggest that binding to the enzyme is primarily mediated by the pyrophosphate moiety assisted by relatively nonspecific lipophilic interactions. Decreasing the chain length and saturating double bonds severely reduces binding, while substitution at the 2,3, and 4 positions, and lengthening of the chain, is well tolerated.
TL;DR: Aryloxy alkyl diketones II was synthesized and screened in vitro for antiviral activity as discussed by the authors, which exhibited a high level of activity against both DNA and RNA viruses in both the tissue culture and organ culture screens and was particularly effective against herpesvirus type 1 and 2.
Abstract: A series of aryloxy alkyl diketones II was synthesized and screened in vitro for antiviral activity The effect of various substituents on the phenyl ring, as well as the length of the alkyl bridge, was examined to establish the requirements for optimum activity One of the most active members of the series, 4-[6-(2-chloro-4-methoxy)phenoxy]hexyl-3,5-heptanedione (56), exhibited a high level of activity against both DNA and RNA viruses in both the tissue culture and organ culture screens and was particularly effective against herpesvirus type 1 and 2
TL;DR: The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4.
Abstract: The optical isomers of alpha-adrenergic receptor antagonists prosympal (2), piperoxan (3), and dibozane (4) were prepared by methods establishing the absolute configuration of each. (2S)-3(2'-Hydroxyphenoxy)-1,2-propanediol ditosylate (10) was prepared from (2R)-3-tosyloxy-1,2-propanediol acetonide (6). Intramolecular displacement afforded (2S)-tosyloxymethylbenzodioxan [(2R)-11]. Reaction of (2R)-11 with the appropriate amine (diethylamine, piperidine, or piperazine) afforded the 2S isomers of 2, 3, and 12, respectively. Reaction of (2S)-12 with (2R)-11 afforded the SS isomer of 4. Reaction of (2S)-3-benzyloxy-1,2-propanediol ditosylate (14) with catechol (NaOMe) afforded (2R)-benzyloxymethylbenzodioxan (15). Subjecting 15 to hydrogenolysis, tosylation, and displacement with the appropriate amine afforded 2R isomers of 2, 3, and 12. Reaction of (2R)-12 with (2S)-11 afforded (RR)-4. Reaction of (2R)-12 with (2R)-11 afforded meso-4. The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4. meso-4 was as effective as the SS isomer of 4. The results are interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen, and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.
TL;DR: A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium, showing modest activity against L1210 leukemia in mice.
Abstract: A series of classical quinazoline analogues of folic and isofolic acids was evaluated for inhibitory activity against the dihydrofolate reductases from rat liver and from Streptococcus faecium. Included in this group were the known active antitumor agents methasquin and chlorasquin as well as methotrexate. Two new compounds, N10-formyl-5,8-deazaaminopterin and N10-formyl-5,8-deazafolic acid, were synthesized specifically for this study. The latter displayed modest activity against L1210 leukemia in mice.
TL;DR: Benzamides characterized by one or more 2,2,2-trifluoroethoxy ring substituents and a heterocyclic amide side chain have been prepared and evaluated for oral antiarrhythmic activity in mice and, within this group, both tertiary as well as secondary benzamides are active.
Abstract: Benzamides characterized by one or more 2,2,2-trifluoroethoxy ring substituents and a heterocyclic amide side chain have been prepared and evaluated for oral antiarrhythmic activity in mice. The most potent compounds are derived from 2,5-bis(2,2,2-trifluoroethoxy)benzamide, and, within this group, both tertiary as well as secondary benzamides are active. Considerable variation in the heterocyclic ring is permissible, but antiarrhythmic activity is strongly influenced by the basicity of the amine nitrogen and the nature of the link between heterocycle and amide nitrogen. One of these compounds, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide acetate (flecainide acetate, USAN), was studied extensively in animals and selected for clinical trial as an antiarrhythmic.