Current Bioactive Compounds - Volume 4, Issue 2, 2008

Medicinal chemistry is a highly rewarding field of study, which essentially provides novel therapeutic agents for the treatment of a variety of human diseases. I am privileged to serve as guest editor and present this intellectually stimulating issue highlighting the medicinal chemistry advancements in critically important health problems such as alzheimer's disease, diabetes, hepatitis C virus infection, and intractable chronic pain. Kharkar and Dutta present a review on neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). They have specifically discussed interactions of redox-active transition metals Cu2+, Zn2+ and Fe3+ in the central nervous system (CNS) with metal-binding proteins such as amyloid-β (Aβ), neuromelanin, etc., leading to increased protein aggregation and oxidative stress followed by initiation/progression of neurodegenerative disorders. They have also provided an in-depth review on metal-protein attenuating compounds (MPACs) such as Clioquinol (CQ) as an emerging therapeutic approach leading to restoration of metal homeostasis, decreased oxidative stress and thereby reversing or slowing CNS disease progression. In this issue, Zito et al., present a thorough review on the chemicals used in the current treatment of type 2 diabetes and discuss some potentially viable, promising targets in the management of this metabolic syndrome, with a special mention to some naturally occurring bioactive compounds. They have also described detailed pharmacological treatment options for type 2 diabetes with a focus on: (1) insulin secretagogues, (2) insulin sensitizers, (3) dipeptidyl peptidase-IV inhibitors, (4) biguanides, (5) α-glucosidase inhibitors and (6) drugs in development. The guest editor of this issue provides an extensive review on structure-based insights on multiple allosteric pockets of HCV NS5B polymerase (a therapeutic target for the treatment of HCV infections) along with detailed structure-activity relationships of several novel nonnucleoside chemotypes binding to different allosteric pockets. This review also addresses potential difficulties surrounding the discovery of future nonnucleoside inhibitors (NNIs) targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes. After providing a brief overview of the Transient Receptor Potential (TRP) superfamily of ion channels, Korlipara focuses the discussion on modulation of TRP Vanilloid 1 (TRPV1) channel, a subject of intense scrutiny by several major pharmaceutical companies over the past decade. The author describes the endogenous and exogenous agents that serve to stimulate the TRPV1 channel and chronicles the highlights in the development of various chemical classes of TRPV1 antagonists. A discussion on the prevailing knowledge regarding the binding sites of the TRPV1 ligands is provided. This review also discusses the potential applications of TRPV1 receptor ligands, particularly, as novel pain therapeutics. As a guest editor, I would like to deeply thank all the contributing authors of this issue for their valuable time and effort. My special thanks also goes to all the experts who have accepted to act as referees of the articles. Their thorough work and criticism have contributed to the success of this issue. Finally I would like to extend personal thanks to Ms. Samreen Laeeq, Manager publications, Bentham Science Publishers for her painstaking cooperation during the entire process of bringing this issue to fruition.

Aberrant interactions of redox-active transition metals Cu2+, Zn2+ and Fe3+ in the central nervous system (CNS) with metal-binding proteins such as amyloid-β (Aβ), neuromelanin, etc., with concomitant increase in oxidative stress leading to consequential neuronal damage are central to the pathology of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and others. The therapeutic significance of metal dysregulation in neurodegenerative disorders has been a subject of intense debate recently. Of the several approaches related to the life cycle of Aβ, metal-protein attenuating compounds (MPACs) represent an emerging therapeutic approach leading to restoration of metal homeostasis, decreased oxidative stress and thereby reversing or slowing the disease progression. MPACs compete with Aβ for binding with redox-active metal ions, subsequently preventing Aβ oligomerization. Clioquinol (CQ), a retired antibiotic, is a prototype MPAC, which has shown encouraging efficacy from early clinical evaluation for the treatment of AD supporting its use. CQ-metal complexes were reported to up-regulate matrix metalloprotease (MMP) activity in vitro. This elevated MMP activity resulted in enhanced degradation of secreted Aβ peptide with additional effect in preventing its aggregation. Few experiments involving mouse model of PD showed neuroprotective effects of clioquinol. This review discusses various issues related to the scientific rationale, scope, evaluation, limitations and applications of MPACs as a novel therapeutic option for the treatment of neurodegenerative diseases.

In this review, we focus on the chemicals used in the current treatment of type 2 diabetes and discuss some potentially viable, promising targets in the management of this metabolic syndrome, with a special mention to some naturally occurring bioactive compounds. Non-insulin dependent diabetes mellitus (NIDDM or Type 2 diabetes) is a prevalent, chronic metabolic disorder, which affects more than 171 million people worldwide. Diminished insulin secretion due to impaired β-cell function and/or insulin resistance of the peripheral tissues such as liver, adipose tissue and skeletal muscle causes hyperglycemia, which is controlled with suitable pharmacological agents. The current line of treatment includes: (1) insulin secretagogues, (2) insulin sensitizers, (3) dipeptidyl peptidase-IV inhibitors, (4) biguanides, (5) α-glucosidase inhibitors and (6) drugs in development.

Infections caused by hepatitis C virus (HCV) are a significant worldwide health problem for which novel therapies are urgently needed. One attractive and viable therapeutic target is HCV NS5B RNA-dependent RNA polymerase (RdRp) since it is essential for the replication of the viral genome of HCV. The hunt for nonnucleoside inhibitors (NNIs) of HCV NS5B polymerase has led to the identification of several allosteric pockets. However, because the topographical features of these binding sites vary across and even within diverse HCV genotypes, the discovery of new antiviral drugs capable of inhibiting HCV RdRp in the face of variable binding pockets becomes a challenging endeavor. This review focuses on recent accomplishments in the development of new NNIs of HCV NS5B polymerase and on their binding mechanisms to the respective allosteric pockets. Potential difficulties surrounding the discovery of future NNIs targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes are also discussed.

The TRPV1 vanilloid receptor, first cloned and characterized in 1997, is a non-selective cation channel expressed in primary sensory neurons, and is a key pain sensor and integrator. Activators of this receptor are varied and include capsaicin, the pungent phenolic principle from hot chilli peppers, endogenous lipid anandamide, noxious heat, and low extracellular pH. Agonists of the TRPV1 receptor have been investigated for development due to their analgesic effect that results from the receptor desensitization. However, all agonists including capsaicin cause initial burning effect, and have the potential for other undesirable effects, which complicates effective therapy. The development of animal pain models involving TRPV1 receptor blockade through small molecules and characterization of TRPV1 “knockout” mice models in recent years has provided a compelling argument in favor of pursuing the development of selective TRPV1 antagonists as novel analgesic agents. This article will provide an overview of the various chemical classes of agonists and antagonists of TRPV1 receptor along with their therapeutic potential and possible side effects.

Lipases are the most used enzymes as biocatalyst in the resolution of chiral compounds. However many times the selectivity towards different intermediates is very low. A simple strategy has recently been reported to permit greatly enhancing the lipase selectivity. The strategy -based on the great conformational changes of these enzymes during catalysis- consists in the preparation of a library of lipase biocatalysts by using different immobilization protocols that may permit to immobilize them via different orientations, with different rigidity or generating different environments. This review examines how this solid phase strategy has permitted greatly modulated the enantioselectivity of lipases in kinetic resolutions of racemic mixtures.