Current Topics in Medicinal Chemistry - Volume 17, Issue 29, 2017

Degenerative diseases are becoming more common with increasing life expectancy of the human population. The 20th century faced a progressive demographic change in the industrialized world, followed by identical trends in population aging in Asia, Africa, and Middle and South America. A significant increase in chronic age-dependent disorders will soon cause important challenges for several countries. Age-related pathologies are commonly seen in elderly patients. More than 40% of adults over 60 years old present a combination of risk factors, described as metabolic syndrome, which significantly increases the tendency for developing degenerative diseases, and some types of cancers. Among these, Parkinson's, Alzheimer's and cardiovascular diseases are on the top of the list. The discovery of effective cardio- and neuroprotective alternative therapeutics that decrease or block disease's progression at early stages, is the main goal of research groups working in the field. A wide range of different substituted coumarins, and the pharmacological properties they may display, are trend topics because of their synthetic accessibility, as well as their abundance in plants and other naturally-occurring products. These heterocyclic compounds play an important role in a variety of areas, but stand out in the field of Medicinal Chemistry. This review provides an overview of the last five years about the potential of coumarins as modulators of several physiological mechanisms involved in age-related pathologies.

Cancer is one of the most serious illnesses of our civilization. The International Agency for Research on Cancer estimated that 14.1 million new cancer cases have been diagnosed last year. Therefore, the cure efficiency of cancer chemotherapy depends not only on how the anticancer drug is delivered to its targets but also on the anticancer drug itself. Among the approved drugs, 80% are derived from natural compounds. In this sense, coumarins, natural polyphenols for which anticancer activity has been proved, can be a source or inspire the synthesis of new anticancer agents. Several natural coumarins, such as scopoletin, daphnetin, esculetin and the less known wedelolactone and galbanic acid, appear to have promising anticancer activities. This paper will provide a comprehensive overview of the advances on natural coumarins with potential therapeutic applications as anticancer agents highlighting the ones for which the mechanism of action is well defined and can serve as lead compounds for the design of new more potent molecules.

This review highlights the promising science that has arisen from the synthesis of novel azaheterocycles from isocoumarins. Specific topics include their synthesis and biological activity. Isocoumarins (1H-isochromen-1-ones) are promising synthons, in particular due to the presence of a deoxybenzoin fragment which opens up wide possibilities for synthetic transformations. The deoxybenzoin cycle is highly susceptible to the action of various nucleophilic agents; its oxygen atom participates in recyclization reactions under the action of N-nucleophiles where it is replaced by a nitrogen atom, making it possible to obtain isoquinolones via a reaction with ammonia, primary amines, hydroxylamine and benzodiazepinones via a reaction with hydrazine. We systematize literature data, including patents (about 60 publications in all), demonstrate the routes of 3- arylisocoumarins modification under the action of N-nucleophiles – ammonia and primary amines, diamines, secondary amines, (het)arylamines, hydroxylamine, and hydrazines, and discuss the practical importance of these studies for medicinal chemistry.

Objective: A new class of ethylene/propylene-1H-1,2,3-triazole-4-methylene-tethered isatincoumarin hybrids 8a-j, integrating three anti-tuberculosis pharmacophores coumarin, isatin and 1,2,3- triazole was designed and synthesized. Method: These hybrids were assessed for their in vitro anti-TB activity against MTB H37Rv and MDRTB, as well as anti-bacterial activity against Gram-positive and Gram-negative strains, and cytotoxicity in VERO cell line. Results: The results showed that all hybrids with acceptable cytotoxicity (CC50: 64-512 μg/mL) exhibited weak to moderate anti-microbial activity. The most active hybrid 8i with MIC of 50 μg/mL against MTB H37Rv and MDR-TB, also has excellent cytotoxicity profile (CC50: 128 μg/mL). Conclusion: The resistance index of hybrid 8i was 1, indicating that hybrid 8i has no cross-resistance with the first-line anti-TB agent. Thus, hybrid 8i could act as a lead for further optimization.

Fungi place a huge burden on global healthcare systems attributed to the fact that fungal infections are responsible for the high morbidity and mortality rates in patients who received stem cell transplantation, antineoplastic chemotherapy, organ transplants or suffered Human Immunodeficiency Virus (HIV) infection. Unfortunately, almost none of the representative anti-fungal agents currently used in clinical therapy are ideal in terms of efficacy, anti-fungal spectrum or safety. Moreover, the rapid development of resistance to existing anti-fungal drugs has further aggravated the mortality and spread of fungi, creating an urgent need for novel anti-fungal agents. The broad spectrum of biological activities and successful usage in clinic made coumarins a promising anti-fungal candidate. Furthermore, hybridization of other pharmacophores with coumarin motif may enhance the anti-fungal efficacy, broaden the anti-fungal spectrum and improve the safety profiles. Thus, numerous coumarin hybrids have been assessed for their anti-fungal activities, and some of them showed promising potency and may have a novel mechanism of action. This review aims to outline the recent development of coumarin hybrids as potential anti-fungal agents and summarize their Structure-Activity Relationship (SAR) to provide an insight for rational designs of more active agents.