Planarity or Nonplanarity: Modulating Guanidine Derivatives as α-Adrenoceptors Ligands.

A theoretical study has been carried out at the M062X/6-311++G(d,p) computational level to search for a rationale on ligands' affinity toward α-adrenoceptors by estimating the nature and strength of intramolecular hydrogen bonds potentially formed (by means of the QTAIM and NBO approaches) as well as the degree of deviation from planarity that could be observed in some of the compounds. Four different families have been studied: thiophen-2-yl, 3-carboxylatethiophen-2-yl esters, 3-cyanothiophen-2-yl, and 2-thiazolyl guanidinium derivatives. In the case of the thiophen-2-yl guanidines not substituted in the 3 position, nonplanarity was always observed, whereas in the thiazole series, intramolecular hydrogen bonds were identified between the guanidinium and the thiazole ring forcing the systems to planarity.

Thiophene/thiazole-benzene replacement on guanidine derivatives targeting α-Adrenoceptors.

Searching for improved antagonists of α-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues.