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Graphical abstract, Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100 mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.

A linear relationship between the C-O-C angle and the molecular dihedral angle in a series of phenoxathi-ins and azaphenoxathiins is reported. 17O nmr spectroscopic data (natural abundance in acetonitrile at 75°C) were obtained on eight cyclic aromatic ethers 1-8, including phenoxathiins, and two model compounds, acyclic aromatic ethers 9 and 10. The chemical shifts of the cyclic aromatic ethers were very sensitive to structural variations and were dependent upon electonic and conformational effects; however, no quantitative relationship between 17O chemical shift and geometric parameters was found.

WE report that mefloquine (2,8-bis-(trifluoromethyl)-α-(2-pipe-ridyl)-4-quinolinemethanol1, see Fig. 1) clinically useful against drug-resistant Plasmodium falciparum malaria (G. M. Trenholme, unpublished), does not significantly bind to calf thymus DNA. This constitutes the first reported case of an active compound in the quinoline–acridine class of antimalarials which does not strongly bind to DNA by intercalation.

A series of N-(3-dimethylaminopropyl)-6-substituted naphtho[2,1-b]thiophenes-4-carboxamides have been synthesized. 6-Substituted naphtho[2,1-b]thiophene-4-carboxylic acids were obtained upon oxidative-photo-cyclization of α-(2-thienyl)-β-arylacrylic acids. The naphtho[2,1-b]thiophene carboxylic acids were converted to the corresponding amides through their acid chlorides or, in one case, by use of 1,1-carbonyldiimidazole coupling of the amine and the acid.

The assignment of the carbon-13 nmr resonances of 3-(aryl)-5-phenylisoxazoles (I) and 3-phenyl-5-(aryl)-isoxazoles (II) in dimethylsulfoxide-d6 has been made. The assignments were made by using model compounds, chemical shift arguments, coupling with fluorine substituents, and shifts resulting from quaternization of the isoxazole ring. A carbon-13 nmr method for distinguishing between I and II which can be produced simultaneously by certain synthetic methods is presented.

The 17O nmr chemical shifts of 20 acetyl and formylthoiphenes, furans, and pyrroles are reported. The chemical shifts qualitatively correlate with the electronic character of the heterocyclic rings. The effect of steric factors are noted for the 17O chemical shifts of alkyl substituted acetylthiophenes and for N-methylpyr-roles.

1,9-Phenazine-bis(dialkylaminocarboxamides) were prepared for screening as potential antimalarials. No significant activity against Plasmodium berghei was observed. The phenazine targets were prepared from 1,9-phenazinedicarboxylic acid by standard methods. The reaction between 1,9-phenazinedicarboxylic acid and thionyl chloride in the presence of dimethylformamide unexpectedly gave 4-chloro-1,9-phenazinedicarbonyl chloride.

Four acenaphtho[1,2-e]-as-triazines and 11 5,6-diaryl-as-triazines, all substituted with an aliphatic or aromatic amino function in the 3-position, were synthesized. Two acenaphthotriazines were active against vesicular stomatitis virus in tissue culture.

The interaction of naphthothiophene, phenanthrene and anthracene ring systems, which have amide and ester side chains with cationic groups (synthesized from the aromatic acid chlorides and appropriate amines and alcohols), with calf thymus DNA has been investigated by using viscometric titrations, spectrophotometric binding experiments and 1H-, 31P- and 17O-NMR methods. The viscosity and NMR experiments suggest that all of these compounds bind to DNA by intercalation. These experiments and spectrophotometric binding studies, however, indicate that there is considerable variation in the interaction of these compounds with DNA. These variations can all be explained by the geometry of the ring systems, the position of protons adjacent to the side chains, and the relative sizes of the amide and ester side chains. With the naphthothiophene ester and amide, for example, the planar amide cannot rotate into the plane of the naphthothiophene ring whereas the smaller planar ester can. With this ring system the ester has a significantly higher binding constant than the amide derivative. Additional binding studies with poly[d(A-T)2] and poly[d(G-C)2] have shown that all of these compounds bind more strongly to the A-T- than the G-C-containing polymer. Since the ester compounds do not have hydrogen bond donating groups proximate to the aromatic ring, these results suggest a model for the A-T specificity of these compounds that involves a solvent-mediated hydrogen bond between the C-2 carbonyl of thymine and the carbonyl group of the intercalators.

A series of N-(3-dimethylaminopropyl)-6-substituted naphtho[2,1-b]thiophenes-4-carboxamides have been synthesized. 6-Substituted naphtho[2,1-b]thiophene-4-carboxylic acids were obtained upon oxidative-photo-cyclization of α-(2-thienyl)-β-arylacrylic acids. The naphtho[2,1-b]thiophene carboxylic acids were converted to the corresponding amides through their acid chlorides or, in one case, by use of 1,1-carbonyldiimidazole coupling of the amine and the acid.

1,9-Phenazine-bis(dialkylaminocarboxamides) were prepared for screening as potential antimalarials. No significant activity against Plasmodium berghei was observed. The phenazine targets were prepared from 1,9-phenazinedicarboxylic acid by standard methods. The reaction between 1,9-phenazinedicarboxylic acid and thionyl chloride in the presence of dimethylformamide unexpectedly gave 4-chloro-1,9-phenazinedicarbonyl chloride.

Description d'une part des relations entre les deplacements chimiques de RMN 17 O et l'angle de torsion entre les groupements fonctionnels contenant un atome d'oxygene et les cycles aromatiques dans un certain nombre de systemes. Ces systemes impliquent des molecules dans lesquelles les interactions de van der Waals sont reduites par rotation autour d'une liaison simple. Etude, d'autre part des deplacements chimiques de RMN 17 O des groupements carbonyle de systemes plans, rigides

A naphthothiophene intercalator with a cationic side chain linked to the ring through an ester group (1E) has been shown to bind to DNA almost an order of magnitude more strongly than a similar compound with the side chain linked to the ring through an amide group (1A) (W.D. Wilson, et al., Biophys. Chem. 24, 101-109 (1986]. X-ray crystallographic analysis of these two compounds indicates that both the ester and amide groups are essentially planar but that the amide is twisted approximately 30 degrees out of the aromatic plane of the naphthothiophene while the ester and ring system are co-planar. Proton NMR studies of the DNA complexes of these two compounds indicate that the naphthothiophene ring is intercalated in both 1A and 1E but that the protons of the ring system near the side chain interact with DNA base pairs at the binding site significantly better in 1E than in 1A. The protons next to the ester group on the side chain of 1E are also shifted upfield significantly more on addition of DNA than those of 1A. The large planar area of 1E, thus, allows greater stacking, complex geometry optimization, and dipolar interactions of the ester group with DNA base pairs at the binding site to account for the larger binding constant of this compound relative to 1A.

Ausgehend von der Dichlorbenzoesaure (I) erhalt man die substituierten Acridine (VI), deren Bindungsaffinitat bestimmt wird.

The efficacies of dicationic carbazole compounds, nitazoxanide (NTZ), and paromomycin were evaluated against the AUCp1 isolate of Cryptosporidium parvum by using a neonatal mouse model. Compounds were solubilized or suspended in deionized water and administered orally by gavage to neonatal mice at a constant dose rate on days 0 to 5 (treatment started on day 0). Dose rates varied for individual carbazole compounds but ranged from 0.65 to 20 mg/kg of body weight. NTZ was tested at 100 and 150 mg/kg, and paromomycin was tested at 50 mg/kg. Efficacies were determined by comparing numbers of oocysts present in treated versus control mice at necropsy examination on day 6. Demonstrable efficacy was observed for several carbazole compounds, based on significant reductions in the numbers of oocysts recovered from treated mice versus control mice. Compounds 1, 7, and 10 (19.0 mg/kg) reduced oocyst passage in treated mice to less than 5% of that in control mice. Treatment with compounds 6, 8, and 9 (17.0 mg/kg) resulted in reductions of oocyst output to less than 10% of that in controls. Although they were not comparable in efficacy to compounds 1, 6, 7, 8, 9, and 10, treatment with other carbazole compounds resulted in statistically significant reductions in oocyst output in treated versus control mice. Compound 1 retained efficacy resulted in reduction of oocyst output to approximately 6% of that in controls when the dose was reduced to 5 mg/kg. Further reductions in the dose rate resulted in considerable reductions in anticryposporidial activity. Likewise, the efficacies of compounds 9 and 10 were reduced substantially when the doses were lowered to one-half the screening dose. Paromomycin yielded excellent activity (reduction of oocyst output to

The 17O chemical shift data, at natural abundance, for selected nitroquinolines, nitroindoles, nitroindazoles and nitrothiophenes are reported. In the absence of a peri or a lone-pair repulsion effect, the nitroquinolines' chemical shifts differ little from those of their carbocyclic analogs. However, the signal for 5-nitroquinoline, 2, is deshielded by 25 ppm compared to 6-nitroquinoline, 1, and the 17O nucleus in 8-nitroquinoline, 3, is deshielded by 49 ppm compared to that in 1. Both these shifts are attributed to rotation of the nitro group from the plane of the heteroaromatic ring arising from peri hydrogen interaction and lone pair repulsion, respectively. The signals for nitro groups on electron excessive ring systems (e.g., indoles and thiophenes) are shielded relative to corresponding ones in electron deficient heterocyclic ring system analogs. The chemical shifts for the π-excessive systems are interpreted in terms of electronic effects.

The synthesis of diethyl-1,3,4,13b-tetrahydro-13b-phenyl-2H-pyrimido[1,2-f]phenanthridine-7,12-dicarba-mate and N,N′-3,3′[5,5′-Bis(3,8-biscarbethoxyamino-6-phenyl)phenanthridinium]propylglutarylamide dichloride are reported starting from 3,8-biscarbethoxyamino-5-(3′-bromopropyl)-6-phenylphenanthridinium bromide.

17 O N.m.r. data for intramolecular hydrogen bonded 2′-amino and amido substituted acetophenones are factored into electronic, torsion angle, and hydrogen bonding components which show that the most acidic proton donor yields the largest shielding effect:MM2 calculations predict consistent hydrogen bonding distances of ∼1.97 A but variation in torsion angles.