New optimized piperamide analogues with potent in vivo hypotensive properties

Abstract 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. 1 H 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.