Synchrotron X-ray powder diffraction data of LASSBio-1515: A new N-acylhydrazone derivative compound

Abstract

In this work, synchrotron X-ray powder diffraction data allowed for a successful indexing of LASSBio-1515 compound, candidate to analgesic and anti-inflammatory activity. X-ray powder diffraction data collected in transmission and high-throughput geometries were used to analyze this compound. The X-ray wavelength of the synchrotron radiation used in this study was determined to be λ=1.55054 Å. LASSBio-1515 was found to be monoclinic with space group P2₁/c and unit cell parameters a=11.26255(16) Å, b=12.59785(16) Å, c=8.8540(1) Å, β=90.5972(7)° and V=1256.17(3) Å³.

Introduction

The N-acylhydrazone moiety was considered as a single molecular framework and as a privileged structure employed to the design of several new lead-compounds with diverse pharmacological activities, including analgesic and anti-inflammatory effects. The works developed at Laboratory of Synthesis and Evaluation of Bioactive Substances (LASSBio^®) of the Federal University do Rio de Janeiro, with N-acylhydrazone (NAH) derivatives, compiled in Fraga and Barreiro's revisions (Barreiro and Fraga, 2001, Fraga and Barreiro, 2006), evidenced the privileged structure character of this bioactive framework. The first series of bioactive NAHs studied at LASSBio^® was rationally planned using Medicinal Chemistry tools concerning molecular modification, such as molecular hybridization (Viegas-Jr et al., 2007), bioisosterism (Lima and Barreiro, 2005), molecular simplification (Barreiro, 2002), homologation and conformational restriction. The employment of such strategies allowed the rational planning of important alterations of the lipophilic character, donor/acceptor H-bonding sites, as well as in the distances and conformational orientations of the respective pharmacophoric groups, creating a differentiation in the molecular recognition pattern of compounds of the same chemical class against different biomacromolecules, which result in distinct selectivity profiles (Wermuth, 1996, Duarte et al., 2007).

Throughout the years several prototypes of new drugs, (NAH) derivatives, have been discovered, including LASSBio-294 (Silva et al., 2002, Silva et al., 2005, Silva et al., 2005, Kümmerle et al., 2009). It is a thienylhydrazone prototype (2″-thienylidene)3,4-methylenedioxybenzoylhydrazine that was described as a potent positive cardio-inotropic agent due to an increase in the Ca²⁺ accumulation in the sarcoplasmic reticulum (Sudo et al., 2001) besides having modest analgesic and anti-inflammatory activity.

Considering the employment of strategies of Medicinal Chemistry, a series of compounds was planned by molecular simplification from LASSBio-294. The benzodioxole fragment of LASSBio-294, which may be important to activity in the cardiovascular system (Sudo et al., 2001, Sudo et al., 2006), was substituted by cyclohexyl group forming LASSBio-1515, as shown in Fig. 1. Accordingly, this approach can improve analgesic and anti-inflammatory activity of this novel N-acylhydrazone.

It is well known, that ligand–receptor interaction is ruled by the entropy and enthalpy components (Hitzemann, 1988). Therefore, the substitution of benzodioxole group can result at loss enthalpy component, as hydrogen bond important for the molecular recognition. However, the cyclohexyl group can improve at entropy component favorable for receptor binding complex.

In order to investigate the geometric configuration and other conformational factors, important to the understanding of the biological results, we have selected LASSBio-1515 and collected X-ray powder diffraction data for this end.

The use of X-rays for determination of three-dimensional atomic arrangements in crystal structures of organic and inorganic compounds is an important stage in the design of new substances as well as in the development of new procedures for the synthesis of the already known compounds (Chernyshev, 2001). Every crystalline solid phase has a unique X-ray powder diffraction (XRPD) pattern, which can form the basis for its identification or determination. The X-ray diffraction has been undoubtedly the experimental technique of greatest importance of the task to reveal the crystal structure (Hull, 1919, Shell, 1963).

The LASSBio-1515 compound was submitted to synchrotron X-ray powder diffraction measurement in order to help clarifying the structural aspects, such as physicochemical properties arising from molecular structure changes, common in medicinal chemistry and carried out to understand the structure-activity relationship. In this work, synchrotron X-ray powder diffraction data allowed a successful indexing of LASSBio-1515 compound, which is the first step in solving the its crystal structure. Moreover, this result will increase our understanding of the spatial arrangement presented in crystal structure that may explain some of its physicochemical properties. It should be mentioned that an ongoing work are being carried out on an attempt to solve its crystal structure.