Mini Reviews in Medicinal Chemistry - Volume 8, Issue 14, 2008

This review article describes the current TB drugs, their merits and demerits as well as the new promising anti- TB agents such as diarylquinolines, oxazolidinones and nitroimdiazoles. It also includes the future development of new antitubercular agents according to the potential drug targets of Mycobacterium tuberculosis and structure-activity relationship studies on important anti-TB drugs.

The increased intake of omega-6 fatty acids together with the widely use of omega-3 supplements in Western diets can affect the host defence against infectious diseases. In the present review we focused on the impact of these fatty acids on salmonella and mycobacteria infection models in animals or in cell cultures. Particular attention was given to the molecular mechanisms involved.

Corticosteroids have represented the mainstay of medical treatment for induction of remission in inflammatory bowel disease. Aim of this paper is to review mechanisms of action, safety and efficacy of beclomethasone dipropionate, a steroid with enhanced topical intestinal activity and low systemic activity, in the treatment of inflammatory bowel disease.

Tricyclic compounds are sometimes considered as synonima of drugs healing central nervous system pathologies, although there are some well known examples of tricyclic derivatives marketed for different indications, such as antihistamines, antivirals and antiulceratives. Following the insertion of tricyclic structures in the “privileged structures” pool, several compounds bearing a central 7-membered ring and two aryl rings at its sides have been reported, and some of them have been progressed to advanced clinical trials. An overview of tricyclic derivatives reported in the literature since 1995, that are investigated for indications not directly related to central nervous system affections, shows the potential of these structures in a broad range of therapeutical indications, going from antiviral and anticancer compounds to the therapy of cardiovascular diseases. Very recent examples confirm the usefulness of tricyclic structures for the modern medicinal chemists.

Dysregulation of apoptosis is a major contributor to the initiation and aggravation of liver injury. Agents that modulate apoptosis may be of therapeutic benefit in a number of liver diseases, and research related to cell type-specific activation or inhibition of apoptotic signaling pathways will provide new strategies for treatment.

An important objective of brain tumor modeling is to predict the progression of tumors so as to provide guidance about the best possible medical treatment to halt or slow the tumor's growth. Such computer models also provide a deeper insight into the physiology of tumors. In addition, one can study various what-if scenarios, for instance, investigating the response of tumors following the administration of a drug or a variety of drugs. Abrupt changes in growth rate can also be important for surgical decision-making. Despite increased interest in modeling techniques, relatively little progress has been made in improving such technologies. One problem is the limited data available from patients, typically 1 to 3 MRI (magnetic resonance imaging) sessions, from which one has to extrapolate the type of tumor so as to successfully predict its evolution over time. Here, the biological and clinical aspects of tumor growth and treatment with surgery, radiotherapy and drugs are discussed in the light of a patient with a brain tumor showing accelerated growth over time. Then, the contributions of mathematical modeling of tumor growth and effects of treatment are presented. Current tumor growth models can be roughly divided in three main categories, (i) cellular and microscopic models that emphasize isolated cell behavior, (ii) macroscopic models that concentrate on the development of cell density over time, and (iii) hybrid approaches that contain elements of both microscopic and macroscopic models. The mathematical theory that underlies these simulation methods is remarkably similar to the physical theory that forms the basis of protein modeling and molecular mechanics tools. A severe limitation of current models is that they are in fact not patient-specific at all.

Persistent pulmonary hypertension of the newborn (PPHN), is defined as a failure of the pulmonary vasculature to relax at birth and consequently of the normal adaptation to extra uterine life of the fetal heart/lung system, resulting in hypoxemia. This condition, occurs in about 1-2 newborns per 1000 live births and despite significant improvements in treatment it is associated with substantial infant mortality and morbidity. Over the years wider application of inhaled nitric oxide (iNO) therapy and improved ventilation strategies including surfactant, high-frequency oscillatory ventilation has led to a decrease in the need for invasive life-sustaining therapies such as extracorporeal membrane oxygenation (ECMO). Mortality rate varies from 10 to 20 % of affected newborns in developed countries, but it is much higher when PPHN is refractory to the above reported therapies or when they are not available. As a consequence, development of new therapeutic strategies for severe PPHN is crucial. In particular, recent studies seem to show that sildenafil, a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance may be a useful therapeutic adjunct to critically ill neonates with PPHN.

Cancer cells undergo mitosis frequently, and many mitotic regulators are aberrantly expressed in these cells. Members of the Aurora family of serine/threonine kinases are expressed during mitosis and carry out vital functions in chromosome alignment, segregation and cytokinesis. Here we review the functions of Aurora-B kinases in mitosis and summarize the current literature on Aurora-B kinase inhibitors. In the process of developing these inhibitors as anticancer drugs, the Aurora kinase inhibitors have also helped to advance our understanding of the role of Aurora kinases in mitosis. The mechanism of action and structure-activity relationship of a selective Aurora-B inhibitor are also discussed. The future may see mechanism guided design of chemotherapy combinations that include these cell-cycle phase-specific drugs. The therapeutic potential of Aurora-B inhibitors is promising.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 19 NCEs marketed in 2007.

In this paper the physiological role of NO and isoforms of NOS in the gastrointestinal tract and the involvement of NO in pathological processes of digestive tract as well as the perspective of therapeutic use of NO-donating drugs and selective inhibitors of phosphodiesterase in the treatment of gastric diseases were presented.