In Medicinal Chemistry, the knowledge, the study and the understanding of the intermolecular interactions inherent to the molecular recognition of a ligand by its target bioreceptor are essential. This is because understanding these interactions, which define the molecular complementarity between the two, is the key to analyze critically structure-activity relationship studies, allowing the optimization of the modulation of a target bioreceptor by a ligand. Thus, it is necessary the constant study and analysis of intermolecular interactions related to the ligand-bioreceptor complexes. In general, these interactions are all electrostatic in nature, being traditionally classified into two large groups, the electrostatic forces themselves (such as those present in ion-dipole or ion-ion interactions) and van der Waals forces. Despite being well known, theoretical and experimental studies have revealed an increasing number of interactions mediated by these forces. This work presents and discusses intermolecular interactions considering “classical interactions” and “new interactions” in the context of Medicinal Chemistry, taking into account their current definitions, some theoretical principles of each interaction and addressing examples in which these interactions were important for complementarity between a ligand and a biorreceptor.

A mistura dos derivados semissintéticos cloridrato da (-)-3-O-acetil-cassina e cloridrato da (-)-3-O-acetil-espectalina, preparada a partir da mistura dos alcalóides (-)-cassina e (-)-espectalina (4:1) obtida de Senna spectabilis, é um potente inibidor da acetilcolinesterase (AChE), assim justificando mais estudos moleculares. Neste sentido, estudos de docking e dinâmica moleculares foram conduzidos neste trabalho com o objetivo de adquirir uma compreensão mais profunda de todos os aspectos estruturais das moléculas cloridratos da (-)-3-O-acetil-cassina e (-)-3-O-acetil-espectalina, as quais diferem em seus potenciais inibidores de AChE. Os dois derivados em estudo apresentaram diversas interações com o sítio periférico aniônico dentro da cavidade catalítica de AChE de Torpedo californica. Entretanto, somente o composto majoritário (-)-3-O-acetil-cassina mostrou interação com a tríade catalítica de maneira significativa. As simulações de dinâmica molecular utilizando água como solvente foram importantes para compreender as interações hipotéticas entre cloridratos da (-)-3-O-acetil-cassina e (-)-3-O-acetil-espectalina com AChE. Os dados obtidos indicam que o composto (-)-3-O-acetil-cassina é o inibidor da enzima mais potente possivelmente devido às suas interações favoráveis com a proteína, com menor custo de dessolvatação. Estes resultados sugerem que o tamanho da cadeia lateral influencia no potencial inibitório das moléculas avaliadas e podem representar o ponto de partida para o desenvolvimento de novos derivados de (-)-3-O-acetil-cassina, objetivando a descoberta de inibidores de AChE mais eficazes.

The mixture of semi-synthetic derivatives (-)-3-O-acetyl-cassine hydrochloride and (-)-3-O-acetyl-spectaline hydrochloride, prepared from the mixture of natural alkaloids (-)-cassine and (-)-spectaline (4:1) isolated from Senna spectabilis, has been shown to be a potent acetylcholinesterase (AChE) inhibitor, thereby prompting further molecular studies. In this sense, docking and dynamic molecular studies were carried out in this work, aiming to acquire a deeper understanding about all the structural aspects of molecules (-)-3-O-acetyl-cassine and (-)-3-O-acetyl-spectaline hydrochlorides, which differ with respect to their AChE inhibitory potentials. Both molecules establish important interactions with the peripheral anionic site within the catalytic gorge of Torpedo californica AChE. However, only the major compound (-)-3-O-acetyl-cassine hydrochloride significantly interacts with the catalytic triad. Explicit-solvent molecular dynamic simulations were conducted in order to gain better understanding about the hypothetical interactions taking place between the semi-synthetic alkaloid molecules (-)-3-O-acetyl-cassine and (-)-3-O-acetyl-spectaline hydrochlorides and AChE. The data obtained in this study indicated that (-)-3-O-acetyl-cassine hydrochloride is the most potent inhibitor of AChE possibly due to the favorable interactions of this molecule with the target protein, with lower desolvation cost. These results suggested that the size of the side chain has an effect on the inhibitory potential of the evaluated molecules and may represent the starting point for the development of new derivatives of (-)-3-O-acetyl-cassine hydrochloride, with a view to the discovery of new effective AChE inhibitors.

The understanding of the scientific basis of the erectile function expanded rapidly the range of therapies for treating erectile dysfunction in recent years. This article reviews the role of dopamine on the erection mechanisms and its importance for new pro-erectile drug design. The ability of dopaminergic agents to elicit penile erection has been described since 1975 and successively confirmed by numerous studies. The development of apomorphine SL (dopaminergic non selective agonist) to enhance erectile function represents a new pharmacological approach to the management of erectile dysfunction using CNS drugs. The search for selective D4 dopaminergic agents is being explored by some research groups and pharmaceutical companies.

In this article are described new bioactive N-acylhydrazone (NAH) derivatives, structurally designed as optimization of aryl hydrazones precursors planned by molecular hybridization of two 5-lipoxigenase inhibitors, e.g. CBS-1108 and BW-755c. The analgesic, antiedematogenic and anti-platelet aggregating profile of several isosteric compounds was investigated by using classic pharmacological assays in vivo and ex-vivo, allowing to identify new potent peripheric analgesic lead, a new anti-inflammatory and an antithrombotic agent. During this study was discovered dozen of active NAH compounds clarifying the structure-activity relationship for this series of NAH derivatives, indicating the pharmacophore character of the N-acylhydrazone functionality.

No âmbito de uma linha de pesquisas que trata do planejamento, síntese e avaliação farmacológica de novos candidatos a protótipos de agentes neuroativos, descrevemos neste trabalho a síntese e avaliação farmacológica de novo análogo do nebracetam contendo a unidade 2-aza-biciclo[3.3.0]octano, planejado como candidato a agente nootrópico útil para o tratamento da doença de Alzheimer. A avaliação das propriedades ao nível dos neurônios do sistema nervoso central utilizando a técnica do "path-clamp" não permitiu evidenciar um perfil de ação central adequado para o novo composto.

As part of a research program aiming at the design, synthesis and pharmacological evaluation of a novel lead-candidates of neuroactive compounds, we describe herein the synthesis and the central profile of a new nebracetam analog having a 2-aza-bicyclo[3.3.0]octane system. The new derivative, designed on the basis of the conformational restriction concept, was synthesized in good yields exploring a diastereoselective reductive-amination and cyclization one-pot sequence. The pharmacological profile of this new compound, investigated by using path-clamp techniques on neurons of the CNS, indicated no effects on these cells.

In this communication we describe a new methodology to Dieckmann cyclization of diethyl adipate (1) and diethyl pimelate (3) applying "push-pull" strategy using anhydrous aluminium trichloride and triethylamine in dichloromethane at room temperature. This method is very efficient, simple, safe and reproducible, giving the corresponding cyclic β-keto ester derivatives in 84% and 71% yield, respectively.