Infectious diseases investment decision evaluation algorithm: a quantitative algorithm for prioritization of naturally occurring infectious disease threats to the U.S. military.

Identification of the most significant infectious disease threats to deployed U.S. military forces is important for developing and maintaining an appropriate countermeasure research and development portfolio.

Antitrypanosomal activities of tryptanthrins.

New drugs and molecular targets are needed against Trypanosoma brucei, the protozoan that causes African sleeping sickness. Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), a traditional antifungal agent, and 11 analogs were tested against T. brucei in vitro.

Short report: floxacrine analog WR 243251 inhibits hematin polymerization.

Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On the basis of their structures, we suspected that these compounds might be good inhibitors of hematin polymerization. Indeed, WR 243251 was as potent and floxacrine was only 2-fold less potent than chloroquine as inhibitors of this process.

Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity.

Camptothecin and four of its 10,11-methylenedioxy analogues were examined for their activity against the pathogenic protozoan Leishmania donovani in vitro. The methylenedioxy analogues were 36- to 180-fold more potent than the parent camptothecin, possessing IC50 values ranging from 160 to 32 nM against the parasite. Our finding that the methylenedioxy camptothecins possess greater activity than camptothecin, which is also the case for other cell types and for the generation of cleavable complex in the presence of DNA and purified mammalian topoisomerase I, prompted us to examine the molecular features of camptothecin and methylenedioxy camptothecin analogues.

Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase.

S-Adenosylmethionine (AdoMet) synthetase (SAMS: EC 2.5.1.

Synthesis and biological evaluation of 4-chloro-3, 5-dinitrobenzotrifluoride analogues as antileishmanial agents.

Desnitro analogues of 4-chloro-3,5-dinitrobenzotrifluoride (chloralin) (2), an in vitro microtubule inhibitor of several Leishmania species, have been synthesized from 2-halo-5-(trifluoromethyl)benzenesulfonyl chlorides 4 and 5. The analogues exhibited moderate to excellent activity when tested against Leishmania donovani amastigotes in vitro. Two representative compounds, 7f and 8, were tested against the Khartoum strain of L.

Chagas' disease: a search for treatment and a question--should the disease be of military concern?

If military forces are required to operate in areas that are endemic for Chagas' disease, the occupation should be of critical concern. These areas, located in Central and South America, are many. The matter is of particular importance because no suitable drug exists to treat individuals who contract the disease.

Simulation analysis of formycin 5'-monophosphate analog substrates in the ricin A-chain active site.

Ricin is an RNA N-glycosidase that hydrolyzes a single adenine base from a conserved loop of 28S ribosomal RNA, thus inactivating protein synthesis. Molecular-dynamics simulation methods are used to analyze the structural interactions and thermodynamics that govern the binding of formycin 5'-monophosphate (FMP) and several of its analogs to the active site of ricin A-chain. Simulations are carried out initiated from the X-ray crystal structure of the ricin-FMP complex with the ligand modeled as a dianion, monoanion and zwitterion.

Antagonism of botulinum toxin-induced muscle weakness by 3,4-diaminopyridine in rat phrenic nerve-hemidiaphragm preparations.

The effects of the potassium channel inhibitor and putative botulinum toxin antagonist 3,4-diaminopyridine (3,4-DAP) were investigated in vitro on the contractile properties of rat diaphragm muscle. In the presence of 100 pM botulinum neurotoxin A (BoNT/A), twitches elicited by supramaximal nerve stimulation (0.1 Hz) were reduced to approximately 10% of control in 3 hr at 37 degrees C.

Drugs that show protective effects from ricin toxicity in in vitro protein synthesis assays.

We used an in-vitro, inhibition of protein synthesis assay (PSI) to test a wide variety of drugs for possible therapeutic use against ricin, a toxic glycoprotein that causes death in animals by inhibiting protein synthesis. Selection of test drugs was based on possible interference with ricin activity at different stages of the toxic process. Most of the drugs tested had no effect on ricin-induced PSI, were toxic when tested alone, or enhanced the toxicity of ricin.

The cytotoxicity of N-Pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide.

The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides and succinimides demonstrated cytotoxicity against the growth of a number of cultured cell lines. The substituted succinimides were more effective than the unsubstituted succinimide derivative in reducing cell growth. On the other hand, phthalimide demonstrated more potent cytotoxicity than its N-substituted derivatives.

Hypolipidemic activity of a series of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimides in rodents.

N-Pyridinyl- and N-quinolinyl-ethyl substituted succinimide and phthalimide derivatives demonstrated significant hypolipidemic activity in rodents lowering both serum cholesterol and triglyceride levels at 20 mg/kg.day i.p.

2-Acetylpyridine thiosemicarbazones. 12. Derivatives of 3-acetylisoquinoline as potential antimalarial agents.

A series of 3-acetylisoquinoline thiosemicarbazones and their related thiosemicarbazides was prepared for evaluation as potential antimalarial agents. The former were synthesized by the reaction of 3-acetylisoquinoline with methyl hydrazinecarbodithioate to give methyl 3-[1-(3-isoquinolinyl)ethylidene]hydrazinecarbodithioate, IV. Displacement of the S-methyl group of this intermediate by the requisite amines gave 3-acetylisoquinoline thiosemicarbazones, V.

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.

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.

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.

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-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).

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).

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.

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.

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.

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.