Mini Reviews in Medicinal Chemistry - Volume 12, Issue 8, 2012

Rocuronium, a non-depolarizing neuromuscular blocking drug has a rapid onset of action, a comparatively low potency and, with a more favourable side effects profile than succinylcholine, it has become a popular alternative to that drug for rapid sequence inductions in anaesthesia. The rocuronium-binding cyclodextrin derivative sugammadex, prepared by per-6 substitution of the primary hydroxyls of γ-cyclodextrin with thiol ether-linked propionic acid side chains to extend the hydrophobic cavity to accommodate rocuronium, is used to reverse neuromuscular blockade by encapsulating the drug as an inclusion complex and removing it from the neuromuscular junction to the plasma. It has recently been suggested that sugammadex might also be of value in the management of rocuronium-induced anaphylaxis and this has been potentially supported by recent case reports. However, before sugammadex can be recommended for this purpose, it is important to establish whether or not the allergenic substituted ammonium groups at each end of the rocuronium molecule in the inclusion complex are masked within the cavity or left exposed for interaction with rocuronium-reactive IgE antibodies in the sera of rocuronium-allergic patients. Detailed experimental strategies and experimental protocols to investigate the allergenic potential of the sugammadex-rocuronium inclusion complex are presented and a possible explanation of the apparently rapid and successful reversal of anaphylaxis by administration of sugammadex is advanced and discussed.

α-Glucosidase (EC 3.2.1.20) enzyme belongs to the glycosidase family enzymes, cleave the glycosidic bond of the oligosaccharides that liberate glucose and its inhibition retards the carbohydrate digestion. In the present review, we have discussed the structural features of different α-glucosidase inhibitors (small molecules) responsible for the inhibitory activities. The reported computational studies including, QSAR, pharmacophore modelling, homology models, docking (with analogs enzymes), etc revealed that the topological, electronic and hydrophobicity properties determine the interactions of those molecules. The aromatic substituents connected with flexible bonds in the molecules have significant effect on the interactions, which may due to the presence of aromatic amino acid residues in the active site. The reported homology modelled and other analogs enzymes (enzymes of other species) also confirmed the existence of aromatic residue (amino acids) especially, histidine, phenylalanine and tyrosine in their active site along with the polar (glutamic and aspartic acids) residues. Multiple sequence alignments of the α-glucosidase enzymes (from different species) described that the abovementioned amino acid residues are present in the active site of all the studied enzymes. Recently, Celgosivir (MIGENIX Inc) is an oral prodrug of the natural product castanospermine used for the treatment of HCV infection by inhibiting α-glucosidase I. BMN-701 is an α-glucosidase inhibitors in the phase I pipeline (BioMarine) for the treatment of Pompe diseases. CKD-711 and CKD-711a are aminooligosaccharide α-glucosidase inhibitors and the in vitro study of CKD-711 showed similar effects to acarbose on porcine intestinal maltase and sucrase (IC50s of 2.5 and 0.5 μg/ml). This review also concluded that many α-glucosidases inhibitors obtained from natural products are used for the treatment of various carbohydrate mediated diseases. The structural analysis of these synthetic and natural derivatives guide for the development of novel semisynthetic/synthetic α-glucosidase inhibitors with free of toxicities.

The importance of Factor Xa and thrombin in thrombosis and haemostasis is widely appreciated in the last years. This understanding logically leads to the concept of Factor Xa and thrombin inhibition as viable and attractive target for the antithrombotic therapy. The following review collects and summarizes information on numerous anticoagulant peptides, proteins, chemical compounds and low molecular weight fragment analogues of natural peptides isolated from hematophagous. Unfortunately, not much data from clinical trials of direct Factor Xa and thrombin inhibitors is available in the present moment. The current information reveals that Factor Xa and thrombin inhibition is a promising approach for prevention and treatment of hemostatic impairments. The synthesis of a low molecular weight synthetic peptide mimetics could be a key point in the fight against many diseases related to haemostatic disorders.

Antimicrobial peptides have been extensively investigated for their potential applications as therapeutics and food biopreservatives. The antimicrobial activity may be impaired by the susceptibility for proteolytic degradation and undesirable interactions of the antimicrobial peptide in the biological environment. Development of nanostructures for entrapment and delivery of antimicrobial peptides may represent an alternative to the direct application of these substances. Lipid nanovesicles have been developed for encapsulation of antimicrobial peptides. Phosphatidylcholine is often employed in liposome manufacture, which is mostly achieved by the thin-film hydration method. Nanofibers may allow different physical modes of drug loading, including direct adsorption on the nanofiber surface or the assembly of drug-loaded nanoparticles. Self-assembled peptides reveal attractive features as nanostructures for applications in drug delivery and promising as antimicrobial agent for treatment of brain infections. Magnetic nanoparticles and nanotubules are also potential structures for entrapment of antimicrobial peptides. Nanoparticles can be also chemically modified with specific cell surface ligands to enhance cell adhesion and site specific delivery. This article reviews the most important nanostructures as promising tools for peptide delivery systems.

Sulfur mustard (SM) is a vesicant chemical warfare agent that persists as a serious menace from the viewpoint of acute and chronic toxicity, simple synthesis and no effective treatment currently being available. The two most deleterious basic molecular mechanisms in SM poisoning are: inflammation and over-activation of poly(ADP-ribose) polymerase and the resulting DNA alkylation. Oxidative stress is the common consequence of these pathway activations. In the present review, the significance of oxidative stress in SM poisoning is discussed along with research on antioxidant therapy as a suitable antidote. The temporal dynamics of the redox imbalance, the antioxidant depletion and impact this has on tissues are described as the pathologies induced by SM. Special attention is paid to ameliorating the damage using low molecular weight antioxidants. Melatonin, epigallocatechin gallate and flavone derivatives, in particular, have been studied in recent experiments. The suitability of these antioxidants for therapy purposes is considered in a separate chapter. The review concludes with a view to the future and the studies needed on antioxidant therapy as a countermeasure to SM poisoning.

Cinnamic acid is an organic acid occurring naturally in plants that has low toxicity and a broad spectrum of biological activities. In the search for novel pharmacologically active compounds, cinnamic acid derivatives are important and promising compounds with high potential for development into drugs. Many cinnamic acid derivatives, especially those with the phenolic hydroxyl group, are well-known antioxidants and are supposed to have several health benefits due to their strong free radical scavenging properties. It is also well known that cinnamic acid has antimicrobial activity. Cinnamic acid derivatives, both isolated from plant material and synthesized, have been reported to have antibacterial, antiviral and antifungal properties. Acids, esters, amides, hydrazides and related derivatives of cinnamic acid with such activities are here reviewed.

There is an up-surge of interest in antioxidants because of their potential use in mitigating a wide array of oxidative stress mediated diseases. In the course of our literature search for diverse functional groups, with utility in the design of potential drugs for preventing oxidative stress related cell injury, we have collected a small literature library of core structures or moieties possessing antioxidant activities. These functional groups can be re-configured into robust antioxidants drug molecules, in their own right, or incorporated into drug structures where the antioxidant capability is required. The lack of single papers presenting a collection of diverse small molecule antioxidant moieties as potential design leads prompted us to write this short review of twenty five such functionalities.

In these years, ordered mesoporous silica materials have shown promising applications in drug delivery system as drug carriers. These carriers with stable mesoporous structure, large surface area, good biocompatibility and tailored size of mesopores exhibit significant property of higher drug loading. However, silica-based mesoporous materials cannot control the release of the loaded drug without modifications. In this paper, we review the recent research work discussing functionalization of mesoporous materials by various components and methods for application in drug delivery systems. All the examples show that these functionalized mesoporous silica-based systems have great potential for a variety of drug delivery applications, specifically in the fields of the drug targeted and controlled delivery systems.

There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, anti-inflammatory, antiallergic, antipsychotic, antimicrobial, antimycobecterial, antitumour, antiviral and antitubercular activities. 1,3,4-oxadiazoles constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations led to the development of new 1,3,4-oxadiazole derivatives. This review article describes the various biological activities associated with 1,3,4-oxadiazole ring system and is useful in guiding the researchers across the world working on this moiety and consequently have been instrumental in the advancement of 1,3,4-oxadiazole chemistry.