Daniel L. Klayman

Berberine derivatives as antileishmanial drugs.

Berberine, a quaternary alkaloid, and several of its derivatives were tested for efficacy against Leishmania donovani and Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine was less toxic and more potent than berberine against L. donovani but was not as potent as meglumine antimonate (Glucantime), a standard drug for the treatment of leishmaniasis. Only berberine and 8-cyanodihydroberberine showed significant activity (greater than 50% suppression of lesion size) against L. braziliensis panamensis.

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.

Inhibition of clinically significant bacterial organisms in vitro by 2-acetylpyridine thiosemicarbazones.

Antibacterial activity of 65 2-acetylpyridine thiosemicarbazones and related compounds was determined by using clinical isolates of nine bacterial genera. Minimal inhibitory concentrations (MICs) of 0.002 to 0.062 micrograms/ml were obtained with 23% of the compounds for Neisseria gonorrhoeae and 0.016 to 0.062 micrograms/ml with 17% of the compounds for N. meningitidis. Staphylococcus aureus was inhibited in the MIC range of 0.125 to 0.5 micrograms/ml by 18% of the thiosemicarbazones, whereas 26% inhibited group D enterococcus with an MIC of 0.25 to 2.0 micrograms/ml. Poor antibacterial activity was shown toward the gram-negative bacilli, i.e., Pseudomonas, Klebsiella-Enterobacter, Shigella, Escherichia coli, and Proteus.

Iron(III) complexes of some thiosemicarbazones derived from 2-acetylpyridine, its 6-methyl derivative and itsN-oxide

SummaryA series of iron(III) complexes of thiosemicarbazones derived from 2-acetylpyridine, 6-methyl-2-acetylpyridine and 2-acetylpyridineN-oxide have been prepared from Fe(ClO4)3 and FeCl3. All of the isolated solids have cations involving two monobasic tridentate ligands, and either perchlorate or tetrachloroferrate(III) anions and are 1∶1 electrolytes. Coordinationvia the pyridine nitrogen (or theN-oxide oxygen), the imine nitrogen and the sulphur atom are confirmed by infrared spectra and x-ray diffraction. The presence of two different iron(III) species is indicated by the electron spin resonance spectra of the tetrachloroferrate(III) solids. E.s.r. along with electronic spectra prove the spin-paired configuration of these cationic iron(III) complexes.

Antiviral Activity of 2-Acetylpyridine Thiosemicarbazones Against Herpes Simplex Virus

2-Acetylpyridine thiosemicarbazone derivatives inhibited the replication of herpes simplex virus types 1 and 2 to a greater extent than cellular deoxyribonucleic acid or protein synthesis.

Copper(II) complexes of thiosemicarbazones derived from 2-acetylpyridine and its n-oxide

Abstract A series of Cu(II) complexes of the thiosemicarbazone, 3-azabicyclo[3.2.2]-nonene-3-thiocarboxylic acid 2-[1-(2-pyridinyl)ethylidene]hydrazide(HL) and the corresponding N-oxide (HLO) have been prepared and characterized. Both ligands undergo deprotonation and appear to coordinate via the thione sulfur, the imine nitrogen and the pyridyl nitrogen (or N-oxide oxygen). A single anionic ligand such as Cl−, Br−, NCS− and N−3 completes the bonding to the Cu(II) center of these 4-coordinate complexes. When the complexes are prepared using Cu(II) perchlorate, the solids isolated contain a neutral thiosemicarbazone ligand as well as the deprotonated ligand. The solids are primarily characterized by IR, electronic and electron spin resonance spectroscopy. In addition, electronic and ESR spectra of their chloroform solutions were recorded. Most of the solids (except the nitrates) were unaltered upon dissolution. Simulation of the solution ESR spectra was used to estimate the coupling constants of the various coordinated nuclei.

Thermal decomposition products of dihydroahtemisinin (dihydroqinghaous)

Abstract Dihydroartemisinin (2), a sodium borohydride reduction produot of artemisinin (1), undergoes themolysis at 190 °C to give desoxyartemisinin (3) and a preponderant decomposition product (4) consisting of 2 epimers 4a, (2S, 3R, 6S)-2-(3-oxobutyl)-3-methyl-6-[(R)2-propanal]-cyclohexanone, and 4b, (2S, 3R, 6R)-2-(3-oxobutyl)-3-methyl-6-[(R)2-propanal]-cyclohexanone.

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.

Intermediate spin iron(III) complexes of N4,N4-disubtituted 2-acetylpyridine thiosemicarbazone

SummaryMagnetic susceptibility and Mössbauer spectroscopy measurements have been carried out on [FeIII(SAm)Cl2], and indicate an intermediate spin state for the ferric ion. The temperature-independent magnetic moment of (4.17±0.05) μB, the quadrupole splitting=4.09 mm s−1 and isomer shift=0.133 mm s−1 are in agreement with such formulation. These studies, together with infrared data, are used to suggest a possible structure of the complex.

Thioureas in the Synthesis of Heterocycles

Publisher Summary The chapter presents the heterocyclic systems prepared from thioureas in order of increasing ring size and in order of increasing numbers of heteroatoms. The heteroatorns have been arranged in the following sequence: Nitrogen, sulfur, oxygen, and other elements. Heterocycles prepared from selenoureas and selenopseudoureas are presented together with their sulfur analogs. Heteropolycycles are discussed in a separate section and are grouped according to general ring type, rather than strictly by ring size. Thioureas are useful in the preparation of two four-membered ring systems: Thietanes and 1,3-thiazetidin-4-ones. The chapter also discusses five-membered rings, six-membered rings, and seven-membered rings. C1yclohcxanones have been employed ill reactions with thioureas to give quinazolines with varying degrees of saturation. A simple preparation of otherwise difficulty prepared heterocyclic ring systems is the cyclization of derivatives of type, resulting from reaction of carbethoxy isotliiocyanate with 2-aminoazaheterocycles to give bridgehead-nitrogen heterobicyclic, s-triazinonethiones.