Current Topics in Medicinal Chemistry - Volume 16, Issue 28, 2016

This review discusses the biological and medicinal significance of one of the most important and interesting heterocyclic ring systems, the pyrimidine and its condensed derivatives. Herein, various physiologically important molecules, as well as, therapeutically used drugs having a pyrimidine or condensed pyrimidine system in their chemical structures, have been covered. The chemistry and synthesis of pyrimidines have also been briefly discussed.

Pyrimidine-fused derivatives traits the inextricable part of DNA and RNA, exhibit indispensable role in numerous biological processes, possessing momentous chemical and biological importance. Pyrimidine-condensed derivatives as the pharmacophore exhibit broad spectrum of biological activities encompassing antitubercular, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, anticancer and anti-HIV. Several retrosynthetic approaches, are available for the synthesis of pyrimidine-fused analogues which offers enormous scope in the field of medicinal chemistry. Ring fused pyrimidine and their innumerable derivatives continue to hold the attention of chemists since their presence in the biologically active resources have been known to elicit additive effects on the bio-efficacy of the molecules. The present review is a concerted effort to congregate information mainly focusing on the comprehensive categorization of pyrimidine ring based on their fusion with five, six, seven and eight-membered ring(s). Moreover, it also puts forward their systematic nomenclature, synthetic strategies, and bioactivities including SAR studies. This review is being put forwarded with an incentive to provide researchers with a comprehensive and updated literature. In addition, the manuscript also brings to light the various pharmacophore designs based on fusedpyrimidine ring system, delving deeper into synthesis and the subsequent generation of new libraries of pyrimidine-fused derivatives including their biological assessments.

Tuberculosis (TB) has been declared as a health emergency due to emergence of resistant strains of M. tuberculosis, multidrug resistant (MDR), extensively drug resistant (XDR) TB strains and totally drug resistant tuberculosis (TDR-TB) reported recently in some parts of the world. Therefore, the current situation necessitates developing new antitubercular agents acting on novel targets for effectively controlling TB. Thymidine Monophosphate Kinase (TMPKmt) enzyme is one such target, which is being explored. This review focuses on Structure Activity Relationship studies (SARs) and computational studies of various nucleotide and nucleoside derivatives of pyrimidine analogs reported as TMPKmt inhibitors.

Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A1, A2A, A2B and A3. In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes. Both agonists and antagonists were used as pharmacological tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compounds have reached clinical phases. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists. A lot of synthetic work was made on this scaffold in order to obtain potent A2A and A3 antagonists. Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions. Nevertheless PTP derivatives are tricyclic compounds with a high molecular weight which exhibit limitations such as poor aqueous solubility and difficult synthetic preparation. With the aim to obtain derivatives with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold. Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivatives, respectively. Synthetic strategies for these compounds were reported, combined with the SAR profile on the adenosine receptors.

The majority of carbocyclic nucleosides are of synthetic origin; nature has provided two of the most interesting compounds, aristeromycin and neplanocin A. Aristeromycin and its modified derivatives are an important group of carbocyclic nucleosides that exhibits a wide range of pharmacological properties such as antiviral, anticancer and antitoxoplasma activities. Especially, aristeromycins are widely used as antiviral agents against human immunodeficiency virus, hepatitis B virus, herpes simplex virus, varicella-zoster virus, influenza virus and hepatitis C virus. These potential antiviral and other biological applications of aristeromycin have motivated new effort in search for novel modified aristeromycin derivatives with improved biological activities. Owing to the importance of aristeromycin and its derivatives, the aim of this review is to highlight the aspects reported on the chemistry and bioactivities of aristeromycins.

Pyridine and pyridine-fused ring systems are ubiquitous in medicinal research and demonstrate such diverse pharmacological benefits as anticonvulsant therapies, treatment for fungal and bacterial infections as well as chemotherapy agents. For example, imidazo[1,2-a]pyridines have exhibited a broad range of activity as antiviral, antibacterial, analgesic, antipyretic, and antiinflammatory agents. Indeed many advances in the development of novel synthetic approaches to the pyridines and their fused counterparts are designed around the relevance of these systems to pharmacological research. Moreover, pyridine-based natural products with interesting biological activity continue to be discovered each year. This article highlights recent (2004-2014) discoveries related to the medicinal and pharmacological significance of pyridines, imidazo[1,2-a]pyridines, quinolones and a few other pyridine-fused compounds and is organized around their type of biological activity.

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.

Matrine is a quinolizidine alkaloid isolated from the roots of Sophora flavescens (Kushen), Sophora tonkinensis, and Sophora alopecuroides (Kudouzi). Matrine and its derivatives have displayed a broad scope of biological properties such as anticancer activity, anti-inflammatory activity, antiviral activity, analgesic effect, anti-fibrotic activity, insecticidal activity, antimicrobial activity, etc. The present review has summarized the biological activities and structural modifications of matrine and its derivatives focused on their N-1 position and lactam ring from 2010 to 2015. In addition, the mechanism of action and structure-activity relationships of matrine and its derivatives are discussed.