Synthesis and antitubercular activity of 3-aryl substituted-2-(1H(2H)benzotriazol-1(2)-yl)acrylonitriles^#

Abstract

A series of 22 3-aryl substituted-2-(1H(2H)-benzotriazol-1(2)-yl)acrylonitriles was synthesized for a preliminary in vitro evaluation of antitubercular activity according to an international program with the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF). This work reports the synthetic approach and analytical and spectroscopic characterization (UV, IR, ¹H- and ¹³C-NMR) of all compounds synthesized. Several compounds showed an interesting activity in the preliminary screening with a percent growth inhibition of the virulent Mycobacterium tuberculosis between 40 and 99% at the concentration of 12.5 μg/mL. The most effective derivatives E-5a and E-5e were also tested against M. avium in vitro.

Introduction

Tuberculosis today still represents one of the major problems for public health world-wide. After a long period in which it seemed to be declining, in the last two decades an unexpected return has been recorded for this disease [1], [2]. This resurgence affected both in developing countries, where infection is endemic, and industrialized countries. In particular, it is generally well accepted that factors which determined the return of tuberculosis in industrialized countries are: the migrant flow from low income countries, the diffusion of HIV infection and the development of multidrug-resistance of Mycobacterium strains. The World Health Organization has estimated that every year about eight million new cases of tuberculosis occur and up to three million individuals die due to this disease [3]. Isoniazid, pyrazinamide, ethambutol, rifampicin and streptomycin, generally used in combination among them, are still today the drugs of choice in the therapy of tuberculosis [4]. However the protracted use in time of these molecules represents the main cause of outbreak of new resistant strains. Therefore, there is an urgent need for the development of new drugs having a mechanism different from those mentioned above. Unfortunately, at present, with the exception of rifampicin, little is known about the mechanism of action and the structure–activity relationship of these drugs and that represents an important obstruction to a rational approach of the research in this field. In spite of these difficulties, the numerous reports in the literature of the last years on this matter give in evidence the renewed interest of researchers for antitubercular agents. Among a large amount of molecules tested for this purpose the heterocycles benzofurane [5], benzothiazole [6], [7], benzoisothiazole [8] and benzimidazole [9], [10], [11] have to be cited for their interesting and promising results. Thus, with this in mind we have taken into account the bioisosteric replacement of those heterocycles with a benzotriazole ring, as a part of our continuous interest for both chemical [12], [13], [14], [15] and biological properties [16], [17], [18], [19] of this heterocycle. For this project, developed in agreement with an international program with the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF), we designed a series of 3-aryl derivatives of 2-(1H(2H)-benzotriazol-1(2)-yl)acrylonitriles of figure 1 which were tested at the Southern Research Institute, GWL Hansen’s Disease Center, Colorado (USA), against Mycobacterium tuberculosis in order to discover a new lead for the development of a new class of antitubercular agents.

In this paper we report the preparation of compounds 5a–i and 6a–i (figure 2) which represent the first part of this project in which we considered preliminarily the characterization of the best substituents connected with the aryl moiety. For this purpose the nature of R was selected within groups with various electron-accepting or donor properties and lipophilic–hydrophilic balance. In particular the electronegative substituents F, Cl, Br and the most electron-withdrawing NO₂ and CF₃ groups were compared either with unsubstituted terms or with those bearing electron-releasing groups such as CH₃ and NH₂. Finally, a COOH group was also introduced which possesses both electron-withdrawing and hydrophilic properties. On the whole the structural features of these compounds allowed us a preliminary evaluation of the structure–activity relationship.