New optimized piperamide analogues with potent in vivo hypotensive properties.
We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. 1H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4'-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates.
de Mattos Duarte
Carolina
C
LASSBio-Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, C.P. 68006, 21944-970, Rio de Janeiro, RJ, Brazil.
Verli
Hugo
H
de Araújo-Júnior
João Xavier
JX
de Medeiros
Isac Almeida
IA
Barreiro
Eliezer J
EJ
Fraga
Carlos Alberto Manssour
CA
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology; D052117:Benzodioxoles; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar
D000470:Alkaloids; D000577:Amides; D000959:Antihypertensive Agents; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; C008922:piperine