Design, Synthesis and Evaluation of Bioactive Privileged Structures for Drug Discovery

Abstract

The drug discovery process mainly depends on the discovery of compounds that cure or help to treat diseases. One of the major goals in drug discovery research is to identify high affinity and specific ligands for receptors and enzymes. The identification of such ligands is an important step in the development of new and better therapeutic agents. Despite the recent developments in small scale and high throughput synthesis on solid supports and in solution for the generation of focussed libraries, the total output of new pharmaceutical entities has not increased significantly and modification in existing strategies for drug discovery are warranted. Besides the screening of sets of new compounds by selected biological assays, the structural modification and improvement of existing active molecules is very attractive, since it deals with compounds that are “druglike” in humans. In this direction, the use of ‘privileged structures’, a single molecular framework able to provide ligands for diverse receptors, concept may be of immense importance to accelerate drug discovery, especially by identifying different targets with unknown 3D structure, i.e. the G-protein coupled receptors. The understanding of the molecular determinants that underline the privileged structure-target relationships should be the key to apply the full potential of the privileged structure concept in the design of novel targeted compounds libraries. Privileged structures have been successfully exploited across and within different target families and promises to be an effective approach to the discovery and optimization of novel bioactive molecules. Moreover, the combination of the concept of privileged structure with the combinatorial chemistry approach can allow a faster identification of a new lead. In alternative to the use of privileged structures, several studies appeared dealing with the preparation of libraries based on the concept of diversity-oriented synthesis. Following this approach, libraries of compounds with rich skeletal and stereochemical diversity were created in order to gain a diverse display of chemical information in three dimensional space. However, no encouraging results are available yet implying that the use of “privileged structures” in the discovery of new drugs can be successfully employed. The thesis entitled “Design, Synthesis and Evaluation of Bio-active Privileged Structures for Drug Discovery” describes our synthetic endeavors towards finding new bioactive molecules. In this direction our prime objective was to design and synthesis of several triarylmethane derivatives as antitubercular agents. Their synthesis and biological evaluation has been described. In another effort, various benzene and isoquinoline sulfonamides were synthesized and evaluated as antimalarials against biological taregts. The work embodied in this thesis has been organized under five main chapters- Chapter I. An Overview on Privileged Structures in Drug Discovery. Chapter II. An Unexpected reaction of phosphorous tribromide on (chromen-4-yl)-aryl-methanols, (thiochromen-4-yl)-aryl-methanols and (2,3-dihydro-benzo[b] thiepin-5-yl)-aryl-methanols: A case study. Chapter III. Design, Synthesis and Antitubercular Activity of Biaryl and Triarylmethane Derivatives. Chapter IV. Design, Synthesis and Antimalarial Activity of Benzene and Isoquinoline Sulfonamide Derivatives. Chapter V. A convenient synthesis of chiral amino acid derived 3,4-dihydro-2Hbenzo[ b][1,4]thiazine derivatives. In the ‘Chapter I’ a brief review on “Privileged Structures” and its significance in drug discovery process has been described. The Chapter describes modern drug discovery process along with its different tools. In the ‘Chaper II’ a novel observation during the reaction of phosphorous tribromide on chroman, thiochroman, 2,3-dihydrobenzo[b]thiepine derived allylic alcohols leading to some unusual products, saturated ketones, exocyclic olefins, and rearranged products is reported. The mechanistic investigation of these unexpected reactions has been described. The ‘Chapter III’ of the thesis deals with the study which has identified triarylmethane derivatives (TRAMs) as a new class of antitubercular in vitro and in vivo. It was observed that thiophene containing TRAMs exhibited better antitubercular activity. In ‘Chapter IV’ design, synthesis and antimalarial activity of a series of benzene and isoquinoline sulfonamide derivatives is described. Selected isoquinoline derivatives with chlorine substitutent on benzene ring exhibited good in vitro antimalarial activity.In ‘Chapter V’, a short and facile synthetic route for the preparation of S-amino acid derived chiral benzothiazine derivatives involving copper-catalyzed intramolecular aryl amination reaction has been described. Brief summary, experimental procedures, spectra of some of the important compounds and appropriate literature citations are given in the text of each chapter of the thesis.