Antifilarial agents. 3-Aminopyrrolidine and 1,4-diazabicyclo[3.2.1]octane derivatives as analogs of diethylcarbamazine

Abstract

3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like antifilarial activity does not require that both pharmacophores be incorporated into one ring. Results with the 1,4-diazabicyclo[3.2.1]octanes establish that an axial conformation of the alkyl substituent corresponding to the equatorial N-methyl group of diethylcarbamazine is fully consistent with high activity. Other conformational consideration pertinent to DEC analogues are discussed.

Quinolone antibacterials: preparation and activity of bridged bicyclic analogues of the C7-piperazine

“…General Method E. (lS-c/s)-l-Cyclopropyl-6,8-difluorol,4-dihydro-7-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-4oxo-3-quinolinecarboxylic Acid (10). A solution of (ISci's)-l-cyclopropyl-6,8-difluoro-7-(2,5-diazabicyclo[2.2.1]hept-2yl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (7; 3.60 g, 9.5 mmol), 85% formic acid (50 mL), and 37% formaldehyde solution (50 mL) was heated to reflux for 4.25 h. After cooling, the reaction mixture was evaporated and the residue was dissolved in hot ethanol and 6 N HC1 in 2-propanol (3 mL) added.…”

Fluorescent Diethylcarbamazine Analogues: Sites of Accumulation in Brugia malayi

“…Early medicinal chemistry studies identified the fundamental importance of the piperazine ring and the 4- N -methyl substituent on the ring (Scheme ). DEC analogues with a range of substituents for the dialkylcarbamyl group show antifilarial activity, but substitution of the methyl and modification of the ring leads to drug inactivity. , …”

“…DEC analogues with a range of substituents for the dialkylcarbamyl group show antifilarial activity, but substitution of the methyl and modification of the ring leads to drug inactivity. (5,6) In this study, we have synthesized new fluorescein and rhodamine B-labeled DEC analogues for use in drug localization studies with confocal microscopy. A high-yield three-step synthesis (Scheme 2) results in the β-amine-substituted DEC analogue 3 in which only a single ethyl substituent is altered, thus preserving the crucial pharmacophore of DEC. (5,6) Compound 3, by attachment to its reactive amine group, can be readily conjugated to fluorescein isothiocyanate (FITC) to give 4 or rhodamine B (RHB) to give 5 (Scheme 3).…”

Syntheses of Enantiopure 3,4-Diamino-1-Substituted Pyrrolidines

“…5 3-Aminopyrrolidines have served as templates for the introduction of essential pharmacophoric groups, 6 and present a relatively conformationally rigid framework suitable for incorporation into anti-filarial agents. 7 trans-3,4-Diaminopyrrolidines have found use in the assembly of numerous systems of specific molecular recognition 8 and as catalysts in enantioselective alkylations, 9 functions that make use of their C 2 symmetry. trans-3,4-Diaminopyrrolidines are also well-suited to development in the context of combinatorial chemistry 10 and have formed the basis of some C-nucleosides.…”