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Biomedical subjects

D L Klayman

Publications and source records attributed to D L Klayman.

At least 37 records · Page 2Linked to original sources
PubMed1986

Stability studies of bis(pyridiniumaldoxime) reactivators of organophosphate-inhibited acetylcholinesterase.

Relative stability studies of three organophosphate-inhibited acetylcholinesterase reactivators, 1-(2-hydroximinomethyl-1-pyridinium)-3-(4-carbamoyl-1-pyridinium)- 2-oxapropane dichloride (HI-6), 1,1'-methylenebis(4-hydroximinomethylpyridinium) dichloride (MMB-4), and 1,1'-trimethylenebis(4-hydroximinomethylpyridinium) dibromide (TMB-4) were carried out by semiquantitative TLC and NMR methods. TMB-4 appears to be the most, and HI-6 the least stable of the three compounds. The extent of hydrolysis of HI-6, MMB-4, and TMB-4 in 0.05 M, pH 7 phosphate buffer was approximately 50, 25, and less than 1%, respectively, after 20 d at room temperature. The hydrolysis products of HI-6 were identified by NMR and MS (electron impact) as 2-pyridinealdoxime, picolinamide, and isonicotinamide, whereas that of MMB-4 was identified as 4-pyridinealdoxime. The stability of these reactivators decreases with increasing pH. TMB-4 was stable under both neutral and basic conditions at room temperature. Deuterium exchange of the methylene protons of MMB-4 in D2O and of the protons at the 2- and 6-positions of the pyridinium ring of TMB-4 in NaOD/D2O were observed.

Acetylcholinesterase↗
PubMed1986

Thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds as inhibitors of herpes simplex virus in vitro and in a cutaneous herpes guinea pig model.

A series of 111 thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds were evaluated as inhibitors of herpes simplex virus in vitro and in a cutaneous herpes guinea pig model. All derivatives tested were potent inhibitors of virus replication with mean 50% inhibitory concentrations of 1.1 micrograms/ml for both type 1 and 2 herpes simplex virus. Inhibitory concentrations for cellular protein and DNA synthesis were considerably higher for many compounds resulting in in vitro therapeutic indices ranging from greater than 100 (highly selective) to less than 1 (negatively selective). All compounds were tested for dermal toxicity following topical administration of saturated solutions in 1,3-butanediol to the shaved, depilated skin of guinea pigs. Approximately 50% of the compounds produced slight to no dermal toxicity whereas the remaining compounds produced moderate to severe dermal toxicity. 28 compounds were evaluated in the cutaneous herpes guinea pig model against herpes simplex virus type 1. A number of N4-monosubstituted 2-acetylpyridine thiosemicarbazones produced highly significant reductions in days to healing and lesion score without producing untoward dermal toxicity. Structure-activity relationships revealed that a reduction of the azomethine bond in the molecule (i.e., conversion of a thiosemicarbazone to a thiosemicarbazide) greatly diminished dermal toxicity apparently without producing a proportional decrease in antiviral activity.

Animals↗
PubMed1986

Antibacterial properties of 2-acetylpyridine-1-oxide thiosemicarbazones.

We have investigated the in vitro antibacterial activity of 13 2-acetylpyridine-1-oxide thiosemicarbazones and 5 thiosemicarbazides against 80 clinically significant bacterial cultures, including 13 isolates with known antibiotic resistance. Of the thiosemicarbazones tested, 5 had minimal inhibitory concentrations (MICs) of 0.25 microgram/ml for Neisseria gonorrhoeae isolates; 1 of these had an MIC range of 0.25-0.5 microgram/ml for the Neisseria meningitidis cultures, and 2 had MICs of 2 and 2-4 micrograms/ml for Staphylococcus aureus and Streptococcus faecalis isolates, respectively. Two of the thiosemicarbazides had MICs of 0.25 microgram/ml for N. gonorrhoeae, whereas 2 others had MICs of 2-4 and 4-8 micrograms/ml for S. aureus and S. faecalis isolates, respectively. The test compounds were ineffective against the gram-negative enteric cultures and the Pseudomonas isolates.

Bacteria↗
PubMed1985

Qinghaosu (artemisinin): an antimalarial drug from China.

The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.

Animals↗
PubMed1985

Charge transfer and oxy radicals in antimalarial action. Quinones, dapsone metabolites, metal complexes, iminium ions, and peroxides.

A mechanism of action is proposed that encompasses almost all of the main categories of antimalarial agents: quinones and precursors, dapsone metabolites, metal complexes of thiosemicarbazones and biguanides, iminium-type ions from acridines and quinolines, and peroxides. The toxic effect of the drugs is believed to result from the generation of reactive oxygen radicals that usually arise via charge transfer. Electrochemical studies (reduction potential and reversibility) were performed on a number of these agents. Reduction potentials range from -0.23 to -1.52 V. It is likely that the in vivo values are appreciably more positive in certain cases.

Aminacrine↗
PubMed1984

2-Acetylpyridine thiosemicarbazones XI: 2-(alpha-Hydroxyacetyl)pyridine thiosemicarbazones as antimalarial and antibacterial agents.

A series of 2-(alpha-hydroxyacetyl)pyridine thiosemicarbazones was synthesized as potential antimalarial and antibacterial agents. Their synthesis was achieved by the condensation of N4-mono- or N4,N4-disubstituted thiosemicarbazides with 2-(alpha-hydroxyacetyl)pyridine. The latter was prepared by selective bromine oxidation of (2-pyridinyl)-1,2-ethanediol. The new compounds show potent inhibitory activity against penicillin-sensitive as well as penicillin-resistant Neisseria gonorrhoeae (MIC, 0.5-0.004 micrograms/mL), against Neisseria meningitidis (MIC, 0.5-0.032 micrograms/mL), and Staphylococcus aureus (MIC, 0.5-2 micrograms/mL). Good in vitro antimalarial effects against Plasmodium falciparum (Smith strain; ID50, 6.7-38 ng/mL) were observed in most of these new agents, but only 3 of 12 compounds exhibit moderate in vivo activity against Plasmodium berghei. These new agents appear to be less toxic to the host and more water soluble than the corresponding 2-acetylpyridine thiosemicarbazones.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones. 8. Derivatives of 1-acetylisoquinoline as potential antimalarial agents.

A series of 1-acetylisoquinoline thiosemicarbazones was prepared in order to evaluate their antimalarial properties. This was achieved by the reaction of 1-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(1-isoquinolinyl)ethylidene]hydrazinecarbodithioate (II). Displacement of the S-methyl group from this intermediate by various primary and secondary amines afforded the desired 1-acetylisoquinoline thiosemicarbazones (III). Thiosemicarbazides in which the azomethine moiety of the latter was reduced could be prepared by the reaction of II with NaBH4 to give methyl 3-[1-(1-isoquinolinyl)ethyl]hydrazinecarbodithioate (VIII). Reaction of VII with the appropriate amine gave 1-[1-(1-isoquinolinyl)ethyl]thiosemicarbazides (IX). Evaluation of the antimalarial activity of series III and IX in mice infected with Plasmodium berghei indicated that cures were attainable at dose levels of 40-160 mg/kg.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones. 9. Derivatives of 2-acetylpyridine 1-oxide as potential antimalarial agents.

In view of the antimalarial activity in mice of 2-acetylpyridine thiosemicarbazones, a series of analogous 1-oxides was prepared for evaluation. Their synthesis was achieved by the reaction of 2-acetylpyridine 1-oxide with methyl hydrazinecarbodithioate to give methyl 3-[1-(2-pyridinyl 1-oxide)ethylidene]hydrazinecarbodithioate (II). Reaction of the latter intermediate with secondary amines afforded the desired 2-acetylpyridine 1-oxide thiosemicarbazones (III). Reduction of the azomethine linkage of II with NaBH4 gave methyl 3-[1-(2-pyridinyl 1-oxide)ethyl]-hydrazinecarbodithioate (IV) whose S-methyl group was then displaced by amines to give a 1-[1-(2-pyridinyl 1-oxide)ethyl]thiosemicarbazide, V. Antimalarial activity of III was evaluated against both Plasmodium berghei in the mouse and Plasmodium falciparum in an automated in vitro test system. In both cases, 2-acetylpyridine 1-oxide thiosemicarbazones were found to be less active than the corresponding de-1-oxide analogues. When compounds V were evaluated against Plasmodium berghei in the mouse, a diminution of activity was similarly seen in comparison to the analogues not bearing the 1-oxide moiety.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones and Mycobacterium leprae.

Four 2-acetylpyridine thiosemicarbazones were tested in mice against Mycobacterium leprae by the kinetic method and found to be nearly inactive in a dosage of 0.05% in the diet. At the same dosage, thiacetazone, as a positive control, exhibited its expected activity.

Animals↗
PubMed1984

2-Acetylpyridine thiosemicarbazones. 10. 2-Propionyl-, 2-butyryl-, and 2-(2-methylpropionyl)pyridine thiosemicarbazones as potential antimalarial agents.

In view of the antimalarial properties observed for many 2-acetylpyridine thiosemicarbazones, a series of N4,N4-disubstituted thiosemicarbazones derived from 2-propionyl-, 2-butyryl-, and 2-(2-methylpropionyl)pyridine was prepared for evaluation against the malaria parasite, Plasmodium berghei, in the mouse. The thiosemicarbazones were made by the reaction of methyl hydrazinecarbodithioate with a 2-acylpyridine to give the intermediate methyl 3-[1-2-pyridinyl)alkylidene]hydrazinecarbodithioates. Reaction of the latter with 3-azabicyclo[3.2.2]nonane, 1-(2-pyridinyl)piperazine, or 1H-hexahydroazepine gave the requisite thiosemicarbazones. The three thiosemicarbazones derived from 3-azabicyclo[3.2.2]nonane were most effective, the greatest potency being exhibited by 3-azabicyclo-[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridinyl)butylidene]hydrazide (4) which cured 4/5 mice at a dose of 160 mg/kg. In contrast to the related thiosemicarbazones derived from 2-acetylpyridine, virtually no toxic effects were observed in the series described here.

Animals↗
PubMed1983

2-Acetylpyridine thiosemicarbazones. 6.2-Acetylpyridine and 2-butyrylpyridine thiosemicarbazones as antileukemic agents.

N4-Monosubstituted and N4,N4-disubstituted thiosemicarbazones derived from 2-acetylpyridine, 2-acetyl-6-methylpyridine and 2-butyrylpyridine, and N4,N4-disubstituted selenosemicarbazones derived from 2-acetylpyridine were evaluated against leukemia P388 in the mouse. Significant antitumor activity (T/C greater than 125%) was observed for members of each class. Enhancement of antitumor activity resulted from increasing the size of the N4-substituent of the thiosemicarbazone moiety. Selenosemicarbazones were less active than the corresponding thiosemicarbazones.

Animals↗
PubMed1983

2-Acetylpyridine thiosemicarbazones. 5. 1-[1-(2-Pyridyl)ethyl]-3-thiosemicarbazides as potential antimalarial agents.

Reduction of the azomethine bond of 2-acetylpyridine thio- and selenosemicarbazones with sodium borohydride readily afforded the corresponding thio- or selenosemicarbazides when they were N4,N4-disubstituted. This conversion failed, however, when the thio- or selenosemicarbazones were N4-substituted or unsubstituted. A more general route to the desired thio- or selenosemicarbazides consisted of reduction with sodium borohydride of methyl 3-[1-(2-pyridyl)ethylidene]hydrazinecarbodithioate to give the 2-pyridylethyl derivative. Displacement of methyl mercaptan from the thio ester moiety of the latter by amines produced 1-[1-(2-pyridyl)ethyl]-3-thiosemicarbazides. These compounds were somewhat more active as antimalarial agents in Plasmodium berghei infected mice than the corresponding thiosemicarbazones; however, the enhancement of activity was accompanied by an increase in toxicity. Compound 7, 3-azabicyclo[3.2.2]nonane-3-carbothioic acid 2-[1-(2-pyridyl)ethyl]hydrazide, is the most potent derivative of 2-acetylpyridine we have evaluated to date.

Animals↗
PubMed1983

Thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1- and 3-acetylisoquinoline and related compounds as inhibitors of clinically significant bacteria in vitro.

Antibacterial activity of 64 thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1- and 3-acetylisoquinoline and related compounds was determined by testing clinical isolates of ten bacterial genera, including some which were antibiotic resistant. Minimal inhibitory concentrations (MICs) of 0.016 to 0.125 microgram/ml were obtained with 26% of the compounds for Neisseria meningitidis and 0.002 to 0.25 microgram/ml with 19% of the compounds for N. gonorrhoeae. Staphylococcus aureus was inhibited in the MIC range of 0.062 to 0.5 microgram/ml by 34% of the thiosemicarbazones, whereas 26% inhibited Streptococcus faecalis with an MIC range of 0.25 to 1.0 microgram/ml. Less antibacterial activity was shown toward the Gram-negative bacilli, i.e., Pseudomonas, Klebsiella-Enterobacter, Shigella, Escherichia coli, Serratia marcescens and Proteus.

Anti-Bacterial Agents↗
PubMed1982

2-Acetylpyridine thiosemicarbazones. 4. Complexes with transition metals as antimalarial and antileukemic agents.

Reaction of the 2-acetylpyridine thiosemicarbazones, 3-azabicyclo[3.2.2]nonane-3-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IIIa), its selenium analogue (IIIb), 1H-hexahydroazepine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (IV), and 1H-octahydroazocine-1-thiocarboxylic acid 2-[1-(2-pyridyl)ethylidene]hydrazide (V) with Cu(II), Ni(II), Fe(III), and Mn(II) salts gave crystalline complexes. Relative to the free ligands, these complexes show reduced antimalarial activity in mice infected with Plasmodium berghei; however, antileukemic properties are enhanced by coordination with the above-mentioned metals.

Animals↗
PubMed1982

Correlations between structure and antimycobacterial activity in a series of 2-acetylpyridine thiosemicarbazones.

The antimycobacterial activity of a new series of 2-acetylpyridine thiosemicarbazones was determined in vitro using Mycobacterium smegmatis ATCC 607. The resulting log minimal inhibitory concentration (mumol l-1) values were plotted against the partition coefficient (log P) values for each compound, and fell on a parabolic distribution curve having a log P opt of 3.0. Compounds having partition coefficients outside the range 2.0 to 4.0 were inactive against M. smegmatis. When similar assays were carried out using M. tuberculosis, M. kansasii, M. marinum, M. simiae, M. avium and M. intracellulare, a similar series of parabolic activity curves were obtained having log P opt values around 4.0. The significance of this shift in the log P opt value obtained using the slow-growing pathogenic mycobacteria compared to that observed with the rapid-growing M. smegmatis is discussed in relation to the structures of the variable substituents of these new 2-acetylpyridine thiosemicarbazone compounds.

Anti-Bacterial Agents↗
PubMed1982

In vitro assessment of 2-acetylpyridine thiosemicarbazones against chloroquine-resistant Plasmodium falciparum.

A series of 2-acylpyridine thiosemicarbazones was evaluated in vitro against a chloroquine-resistant Plasmodium falciparum strain. Antimalarial activity was assessed by the inhibition of uptake of [G-3H]hypoxanthine by the parasites. Among the mono- and disubstituted derivatives tested, 13 of 17 had 50% inhibitory doses of less than 10 ng/ml. Increasing the size of the ring at N4 from four to five, six, and seven members produced concomitant decreases in activity. Similarly, increasing the size of the aliphatic substituent on the azomethine carbon reduced activity. Selected compounds were also tested against a chloroquine-susceptible strain. The results suggested that the activities of these agents were not modified significantly by resistance to chloroquine. In general, in vitro activities correlate poorly with the in vivo activities in mice infected with Plasmodium berghei.

Animals↗
PubMed1982

Activity of 2-acetylpyridine and 2-acetylquinoline thiosemicarbazones tested in vitro in combination with other antituberculous drugs.

Determinations of minimal inhibitory concentrations (MIC) were carried out using three new 2-acetylpyridine and two new 2-acetylquinoline thiosemicarbazones tested against Mycobacterium tuberculosis, M. kansasii, M. simiae, M. avium, and M. intracellulare. Two of the compounds (Compounds L and 3I) exhibited MIC less than or equal to 5 micrograms per ml for all of the test organisms, except for M. simiae, which was resistant to most antituberculous drugs. The other thiosemicarbazones (Compounds 3L, 2N, 3G, and 2H) were relatively inactive against the nontuberculous mycobacteria. Rifampin, amikacin, and clofazimine were active when tested singly or in combination with Compounds L and 3I. Addition of compound 3I to a mixture of rifampin, amikacin, and clofazimine resulted in combination MIC of less than 0.6 microgram/ml against all of the nontuberculous mycobacteria, suggesting that combinations of this type may be suitable for the treatment of infections caused by these highly drug-resistant organisms.

Antitubercular Agents↗