Mini Reviews in Medicinal Chemistry - Volume 13, Issue 10, 2013

Nociceptinergic system has become an important target for drug development since the identification of the “orphan”, opioid-like-1 receptor and the isolation of its endogenous agonist nociceptin. Involvement of nociceptinergic system has been verified in a wide range of pathophysiological processes. A large number of nociceptinergic agonists and antagonists with peptide and non-peptide structures have been developed. Several non-peptide nociceptinergic antagonists have recently shown effective on different animal models of parkinsonism. Neuropharmacological background for antiparkinsonian effect of nociceptinergic antagonists, experimental models with high predictive value, nociceptinergic antagonists shown to have potential effect in Parkinson’s disease are summarized. Medicinal chemistry data (logP and TPSA) of the NOP receptor antagonists which are found to be effective in animal models of Parkinson’s disease are provided.

Anti-angiogenic therapy represents a very promising approach in cancer treatment, as most tumors needs to be supplied by a functional vascular network in order to grow beyond the local boundaries and metastatize. The accessibility of vessels to drug delivery and the broad spectrum of cancers treatable with the same compound have arisen interest in research of suitable molecules, with several, especially targeting the VEGF pathway, entered in clinical trials and approved by the Food and Drug Administration. Despite good results, the major hurdle resides in the limited duration of an effective clinical response before tumors start to grow again. Thus, researchers are looking for different alternative targets for a combined and parallel multi-targeting of angiogenic signaling circuits. Activin Receptor-like kinase 1 (ALK1) is a TGF-β type I receptor with high affinity for the BMP9 member of Bone Morphogenic Proteins superfamily: it is expressed mainly, even if not exclusively, on endothelial cells and seems to be involved in the regulatory phase of angiogenesis. Despite a non-completely elucidated mechanism, the targeting of this pathway, both by a soluble ALK1-Fc receptor developed by Acceleron Pharma and by a fully human monoclonal antibody developed by Pfizer, has achieved encouraging results. After having briefly summarized the state of the art of anti-angiogenic therapy, we will first review existing evidence about the molecular mechanisms of ALK1 signaling and we will then analyse in detail the pre-clinical and clinical data available about these two drugs.

Chagas’ disease, caused by the intracellular protozoan Trypanosoma cruzi, is one of the most serious health problems throughout South America. Despite the progress that has been made in the study of its biochemistry and physiology, more efficient chemotherapies to control this parasitic infection are still lacking. In this paper we report the trypanocidal and cytotoxic activities of a series of sesquiterpene lactones, isolated from Asteraceae medicinal plants. The significant trypanocidal activity and high selectivity indexes found for many of the compounds evaluated, prompted us to undertake a quantitative structure-activity relationship study. A model using 3D molecular descriptors allowed us to set up a high correlation of the observed activity and the atomic spatial arrangement of these sesquiterpene lactones closely related to steric parameters.

6H-Indolo[2,3-b]quinoxaline, a planar fused heterocyclic compound exhibits a wide variety of pharmacological activities. The mechanism of pharmacological action exerted by these compounds is predominantly DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is an important parameter for the elucidation of anticancer, antiviral and other activities. This thermal stability of the 6H-indolo[2,3- b]quinoxaline–DNA complex depends on the type of substituents and side chains attached to the 6H-indolo[2,3- b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. Highly active 6H-indolo[2,3-b]quinoxaline derivatives such as NCA0424, B-220 and 9-OH-B-220 have shown good binding affinity to DNA as evident from high thermal stability of compound-DNA complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme but have significant MDR modulating activity. This review establishes ‘6H-indolo[2,3-b]quinoxaline’ as a valuable template for design and development of novel molecules with different biological activities.

Benzimidazole plays an important role in the medicinal chemistry and drug discovery with many pharmacological activities which have made an indispensable anchor for discovery of novel therapeutic agents. Substitution of benzimidazole nucleus is an important synthetic strategy in the drug discovery process. Therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize novel therapeutic agents. Therefore, it is required to couple the latest information with the earliest information to understand the current status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for the development of SAR on benzimidazoles for each activity. This article aims to review the work reported, chemistry and pharmacological activities of benzimidazole derivatives during past years.

Biofilms prevail in natural and man-made environment on all surfaces. They play a beneficial role in water treatment, waste management and are important reservoirs of pathogens involved in fouling of medical and industrial equipments. Biofilms are resistant to antimicrobial agents and there is a lack of understanding in combating these communities. With the advent of dendrimer this scenario has shown promising change. Dendrimers are complex 3D structure molecules that provide well defined functionality with potential application. Although the studies regarding dendrimer technology are in infancy it serves as an attractive feature for drug encapsulation, binding and delivery to the target site. The synthesis of dendrimers is cumbersome and suffers from certain shortcomings such as extensive purification, lower yield and steric hindrance. However, these drawbacks are overcome by engineering alteration in the dendritic structure. In this review we focus on the biological application of dendrimer derived from peptide, carbohydrate, quaternary ammonia and metal ion in inhibiting biofilm formation and antimicrobial activities.

Melatonin, an endogenous ligand for melatonin receptor, plays an important role in modulating various physiological activities through acting on different subtypes MT1, MT2 or the binding site MT3. The distinct roles of the receptor subtypes provide great potential for receptor-specific pharmacological agents. Melatonin has no subtypeselectivity, so it is very important to develop different subtype-selective ligand for receptor subtype research and drug development. In order to provide guidance for developing high selective ligand, this paper focused on the MT2-selective ligands, which developed well in the past years. The MT2-selective ligands, mainly focusing on binding data on MT1 and MT2 receptor, are reviewed in detail according to their structural classes, and the relative pharmacophore, receptor binding models and the relationship between the structure of ligand and the affinity along with selectivity for receptor subtype were discussed, which may facilitate the exploration of more potent and effective MT2-selective ligands.

Prostate cancer is the most common malignancy among men found to be the second leading cause of male cancer-related mortality due to development of resistance against androgen deprivation therapy (ADT). With the advancement in understanding of prostate cancer, numbers of agents have been emerged to target Androgen-Receptor (AR) signaling for the treatment of castration resistant prostate cancer (CRPC). Food and Drug Administration (FDA) has recently approved enzalutamide (XTANDI) for the treatment of CRPC. Androgen receptor promotes the prostate cancer progression after transformation. Androgen receptor signaling leads to CRPC when cellular nucleus binds to DNA and increases pro cancer gene expression. In phase ΙΙΙ clinical trial, enzalutamide showed that 160 mg once daily oral administration is well tolerated and significantly enhanced overall survival in men with CRPC after chemotherapy, demonstrated by reduction in the serum prostate specific antigen (PSA) level and increased survival rate by 4.8 months.

Recently more and more attention is paid to the rare earth metal complexes, because the properties of the rare earth metals are similar to those of the transition metals such as the similar atomic and the ionic radius. A large number of rare metal complexes were synthesized, and their bioactivities were also studied. This review highlights recent researches on the interaction of some rare earth metal complexes with DNA, analyzes how the configuration of the complexes influences the binding affinity, and focuses on the pharmacological activities of the complexes, such as anticancer, antibacterial, antioxidant, anti-inflammatory and anti-virus.

The development of effective and versatile delivery systems for the controllable and/or targeted delivery of drugs, genes and proteins has a huge potential to improve the disease outcomes. Many drug carriers have been described for different applications in this field. As one of the most reliable alternatives, calcium phosphate (CaP) nanoparticles have been paid so many attentions due to their high bioactivity, biocompatibility, chemical stability and strong adsorption ability under physiological conditions. Some of these properties can in principle be tailored through surface modification, structural design to achieve a sustained, controlled, pulsed or targeted release of drug. In the present article, researches performed in CaP nanoparticles are reviewed based on the recent references.

In the present research, anti-inflammatory and analgesic activities of the synthesized agents derived from Ugi four-component reaction (Ugi-4CR) have been described. The synthesis was initiated by the imine formation under microwave irradiation. Ugi-4CR adducts has been achieved by the condensation of imine with aromatic aldehyde, 4- aminoantipyrine and ethylisocyanoacetate. The reaction was carried out at room temperature in presence of Fluorite as a catalyst. The novel Ugi derivatives were characterized on the basis of IR, 1H NMR, 13C NMR, Mass and Elemental analysis. All the synthesized agents were screened for their potential anti-inflammatory and analgesic activities using healthy wistar albino rats. Anti-inflammatory and analgesic activities were evaluated by Mercury displacement and Hot plate method using Diclofenac and Morphine Sulfate as standard reference drugs respectively. The screening data shows that synthesized compounds are potent agents to act as analgesic and anti-inflammatory drugs.

An overview of docking models of chain arylpiperazines to different subtypes of serotonin receptors belonging to the GPCR family is presented. The theory of a ligand-receptor interaction has been briefly summarized. The review covers more than twenty models, beginning with the early models of a ligand interaction with the 5-HT1A and 5-HT2A receptor, and ending with a ligand-5-HT7 receptor docking studies.