A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

Little has been done during the past 100 years to develop new antileishmanial drugs. Most infected individuals live in poor countries and have a low cash income to be attractive targets to pharmaceutical corporations. Two heterosidic steroids, solamargine and solasonine, initially identified as major components of the Brazilian plant Solanum lycocarpum, were tested for leishmanicidal activity. Both alkaloids killed intracellular and extracellular Leishmania mexicana parasites more efficiently than the reference drug sodium stibogluconate. A total of 10 µM each individual alkaloid significantly reduced parasite counts in infected macrophages and dendritic cells. In vivo treatment of C57BL/6 mice with a standardized topical preparation containing solamargine (45.1%) and solasonine (44.4%) gave significant reductions in lesion sizes and parasite counts recovered from lesions. Alkaloids present different immunochemical pathways in macrophages and dendritic cells. We conclude that this topical preparation is effective and a potential new and inexpensive treatment for cutaneous leishmaniasis.

Podophyllotoxin analogs. 1. Synthesis and biological evaluation of certain trans-2-aryl-trans-6-hydroxymethyl-3-cyclohexenecarboxylic acid gamma-lactones as antimitotic agents.

A series of cis and trans bicyclic lactones was prepared as congeners of podophyllotoxin (1) and evaluated as antimitotic agents both in cell cultures grown in vitro and in an in vitro protein binding assay. All compounds displayed insignificant activity-a result which may reflect insufficient structural similarity to podophyllotoxin or which may be interpreted as in agreement with previous observations of the stereochemical requirements for antimitotic activity defined for 1.

Synthesis and antimalarial activity of (+)-deoxoartemisinin.

(+)-Deoxoartemisinin (2), a new and more active antimalarial agent, was successfully prepared from artemisinin in one step using NaBH4 and BF3.Et2O in THF. (-)-Deoxodeoxyartemisinin (5), a potential metabolite of deoxoartemisinin, was also prepared either from 2 or from artemisinic acid. 2 shows 8-fold increased antimalarial activity in vitro against chloroquine-resistant malaria as compared to artemisinin (1). Compound 2 possesses superior in vivo antimalarial activity to 1.

Transformation of jervine by Cunninghamella elegans ATCC 9245.

Preparative-scale fermentation of the known C-nor-D-homosteroidal jerveratrum alkaloid jervine with Cunninghamella elegans (ATCC 9245) has resulted in the isolation of (-)-jervinone as the major metabolite. In addition, C. elegans ATCC 9245 was able to epimerize C-3 of jervine, producing 3-epi-jervine. This epimerization reaction was similar to that reported for tomatidine, the known spirosolane-type Solanum alkaloid. The structure elucidation of both metabolites was based primarily on 1D- and 2D-NMR analyses.

Pregnane glycosides from Stapelia variegata.

Eleven new pregnane ester glycosides have been isolated from the aerial parts of Stapelia variegata. Eight of the recognized compounds were established to possess the same trioside moiety, viz. 3-O-[3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1-4)-beta-D- cymaropyranosyl-(1-4)-beta-D-cymaropyranoside]. These compounds were identified as: stavaroside A: 12-O-beta-angeloyl-20-O-benzoyl sarcostin; stavaroside B: 12-O-beta-angeloyl-20-O-tigloyl sarcostin; stavaroside C: 11 alpha-acetoxy 2 beta-benzoxy-3 beta,8 beta, 14 beta-trihydroxy-pregn-5-ene-20-one; stavaroside D: 11 alpha-acetoxy- 12 beta-tigloxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5-ene-20-one; stavaroside E: 12-O-beta-benzoyl sarcostin; stavaroside F: 11 alpha-acetoxy-12 beta-acetoxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5- ene-20-one; stavaroside G: 12-O-beta,20-O-diacetyl sarcostin and stavaroside H: 3 beta, 8 beta, 11 alpha, 12 beta, 14 beta-pentahydroxy-pregn-5- ene-20-one. The other three compounds were shown to possess the same tetraside sugar moiety, viz. 3-O-[beta-D-glucopyranosyl- (1-4)-3-O-methyl-6-deoxy-beta-D-allopyranosyl-(1-4)-beta-D-cymaropyra nosyl- (1-4)-beta-D-cymaropyranoside]. These compounds were identified as: stavaroside I: 1 alpha, 12 beta-angeloxy and benzoxy-3 beta,8 beta,14 beta-trihydroxy- pregn-5-ene-20-one; stavaroside J: 11 alpha-acetoxy-12 beta-benzoxy-3 beta, 8 beta,14 beta-trihydroxy-pregn-5-ene-20-one and stavaroside K: 11 alpha-acetoxy-12 beta-tigloxy-3 beta,8 beta,14 beta-trihydroxy-pregn-5-ene- 20-one. The structural elucidation of the isolated compounds was aided significantly on the basis of the chemical and spectral evidence. The decisive assignments of the ester positions were based on the Inverse Detected-Heteronuclear Multiple Bond Connectivity (HMBC) experiments.

Preparation of potential anti-inflammatory agents from dehydroabietic acid.

Methyl 16-nor-16-carboxydehydroabietate (22), 16-nor-16-carboxydehydroabietinol acetate (23), methyl 7-keto-16-nor-16-carboxydehydroabietate (29), 16-nor-16-carboxydehydroabietic acid (30), 16-nor-16-carboxydehydroabietinol (31), 7-keto-16-nor-16-carboxydehydroabietic acid (32), methyl 7-hydroxy-16-nor-16-carboxydehydroabietate (33), and 7-hydroxy-16-nor-16-carboxydehydroabietic acid (34) were prepared from dehydroabietic acid. Only 22 and 32 had weak anti-inflammatory activity.

Differential metabolism of the enantiomers of primaquine.

When racemic primaquine was administered to rats, the majority of the residual primaquine excreted in urine was found to be the (+)-isomer. Using a liver microsome preparation, there was no selectivity in the metabolism of the (+)- and (-)-isomers; however, a liver fraction containing mitochondria and microsomes did show selectivity. In the latter preparation, there was a marked preference for the conversion of (-)-primaquine to (-)-carboxy-primaquine.

Picrotoxin-like lactones.

Preparation of some simple lactone analogues of picrotoxin and their biological evaluation is reported. Certain analogues possessed activity, but at potencies insufficient to warrant further work.

Bromo-6-methoxy-8-aminoquinolines: preparation and 13C-NMR assignments.

Preparation of all possible monobromo-6-methoxy-8-aminoquinolines is reported. These materials provided an opportunity to assess the effect of bromine substitution on 13C-NMR chemical shift patterns. An explanation of the isomerization of 5-bromo-6-methoxy-8-acetamidoquinoline to 7-bromo-6-methoxy-8-aminoquinoline during hydrolysis is presented.

Simple analogs of the toxin callicarpone.

Callicarpone, a component 10 times as toxic to fish as rotenone, has been isolated from the leaves of Callicarpa candicans. It is reasonable to assume that callicarpone will act as an insecticidal agent as does rotenone. Therefore, the structure-activity relationship of callicarpone was examined by synthesizing a series of compounds having certain of its structural features. Those compounds were tested for insecticidal and antimicrobial activities. A study of synthetic analogs elucidated the functional group chemistry of callicarpone so that a synthesis might be undertaken. Piperitone oxide showed approximately 1/100th the activity of rotenone against Daphnia magna. 1-(alpha-Hydroxyisopropyl)-3-oxocyclohexene oxide showed activity against myobacterium while 2,3,4,6,7,8-hexahydronaphthalene-1,4-dione showed inhibitory activity against the mycobacterium and two yeasts.

Simple epoxide analogs of trichothecans.

To define clearly the epoxide grouping role in trichothecan biological activity, a series of hindered epoxides was prepared. They possessed alpha, alpha'-substitution reminiscent of the epoxide environment of the natural products. None of these analogs demonstrated biological activities similar to the natural toxins.

Excretion, distribution, and metabolism of primaquine in rats.

The metabolism of the 8-aminoquinoline antimalarial drug, primaquine (I) was studied using rats. The drug was administered intravenously, intraperitoneally, and orally, and blood samples were collected at various time intervals. Primaquine was metabolized by oxidative deamination to give 8-(3-carboxy-l- methylpropylamino )-6- methoxyquinoline (III). The plasma levels of both primaquine and its metabolite were determined by HPLC. The tissue distributions of radioactive primaquine after intravenous, intraperitoneal, and oral administrations were also determined. Significant concentrations of radioactivity were found in the lungs, adrenal glands, and liver. In addition, a significant portion of the dose was found to be excreted in the feces within 24 h after administration of the drug by either of the three routes.

Nonsurgical management of an isolated interhemispheric subdural hematoma sequentially followed by CT.

Using transaxial CT scan, we diagnosed a patient with head injury as having an isolated interhemispheric subdural hematoma, on the basis of the widening of the superior sagittal sinus. The diagnosis was confirmed by coronal views. The patient was managed nonsurgically and gradual reabsorption of the hematoma was documented by CT. During the latter stages of reabsorption, two parallel lines were noted on the transaxial views as the subdural collection became smaller and drew away from the sagittal sinus. We conclude that an unusual widening of the superior sagittal sinus on transaxial CT scan warrants suspecting an interhemispheric subdural hematoma. Because the hematoma may be obscured by the overlying clot, coronal views may also be valuable.

Time course and inhibition of stavaroside K, veratramine and cevine-induced hemolysis by other pregnane glycosides and Veratrum alkaloids.

Stavaroside K, veratramine and cevine induce hemolysis, whereas 7 other pregnane stavarosides and 8 Veratrum alkaloids are not hemolytic. On the other hand, erythrocytes pretreated or incubated with low concentrations of stavarosides D-F or with the 8 other Veratrum alkaloids were resistant to hemolysis induced by authentic saponin, stavaroside K, cevine or veratramine. Veratridine, zygadenine and angeloylzygadenine (the known Na-Channel-Gate toxins) revealed the most potent reduction of hemolytic activity.

Synthesis and biological activity of new potential antimalarial: 1H-pyrazolo[3,4-b]pyridine derivatives.

The appearance of drug resistant Plasmodium falciparum malaria necessitates the search for novel antimalarial agents. Using the classical ring-bioisosterism concept as a strategy to develop new potential drugs, 1H-pyrazolo[3,4-b]pyridine 4-aminomethanol compounds were designed and synthesized as isosteres of the classical quinoline antimalarial mefloquine. The hydrochloride form of these compounds were tested for in vitro antimalarial activity against chloroquine-sensitive (Sierra Leone D-6) and resistant (Indochina W-2) clones of P. falciparum. The results described herein indicated that 1-H-pyrazolo[3,4-b]pyridine system represents a bioisosteric framework to quinoline system in the antimalarial activity.

Considerations about the structure-activity relationships of 8-aminoquinoline antimalarial drugs.

A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism of action of 8-aminoquinoline agents has not yet been established and thus any analysis of SAR must be speculative.