Central Nervous System Agents in Medicinal Chemistry - Volume 15, Issue 1, 2015

Pyrimidine and its derivatives are present in many of the bioactive aromatic compounds that are of wide interest because of their diverse biological and clinical applications. The utility of pyrimidines as synthon for various biologically active compounds has given impetus to these studies. The review article aims to review the work reported on pharmacological activities of central nervous system (CNS) such as anticonvulsant and antidepressant, which created interest among researchers to synthesize variety of pyrimidine and their derivatives. The present study shows, objective of the work can be summarized as pyrimidine derivative constitute an important class of compounds for new drug development. These observations have been given novel idea for the development of new pyrimidine derivative that possess varied biological activities. This article aims to review the recent works on pyrimidine moiety together with the biological potential during the past year.

From last few years research work on heterocyclic compound and their derivatives has been increasing. Benzothiazole molecule has a heterocyclic structure, basic in nature with wide variety of active sites. As a small molecule, it contains electronegative atoms due to which it is feasible for other moieties to form conjugates. Referring to the bioorganic and medicinal chemistry, the moiety has potential to give active pharmacophores to develop new therapeutically important compounds. Benzothiazole derivatives were found to exhibit efficacy against some very serious diseases like cancer, neurodegeneration, neuropathic pain, infectious diseases, epilepsy etc. In the present review, antiepileptic profile of benzothiazole derivatives is emphasized.

The search for new anticonvulsant agent with more selectivity and lower toxicity continues to be an area of rigorous investigation in medicinal chemistry. Epilepsy is a chronic disorder of brain whose treatment consists of controlling seizures with antiepileptic drugs that very often related with side-effects which in rare circumstances can be potentially life-threatening. Triazolam and Alprazolam are established drugs used in epilepsy which have triazole moiety. The potency and broad spectrum of the pharmacological response of triazole moiety as anticonvulsant agent have attracted the attention of medicinal chemists to explore this framework for its potential. The literature shows that different substitution on triazole ring exhibit potent antiepileptic activity with no or lesser neurotoxicity. The present review is a sincere attempt to compile the reported potent triazole derivatives with significant anticonvulsant action.

A heterocyclic compound is one which possesses a cyclic structure with at least two different kinds of hetero atoms in the ring. Nitrogen, oxygen, and sulphur are the most common heteroatoms. Derivatives are an important class of heterocyclic compounds and play a vital role due to their wide range of biological activities and industrial importance. 4-Thiazolidinones have always been an attraction point for researchers because of their efficiency towards various pharmacological usages. This review is an endeavor to highlight the progress in the central nervous system activity of the 4-thiazolidinone derivatives.

Isatin is a heterocyclic moiety which can be used for the synthesis of a large variety of heterocyclic compounds such as quinolines, indoles and as raw material for medicinal important drugs. This review gives an overview of the advances of isatin for the synthesis of various heterocyclic compounds and shows the various biological potentials such as anticonvulsant, sedative, hypnotic, monoamine oxidase inhibitors, antianxiety, antipsychoactives activity etc. Isatin derivatives displayed as potent anticonvulsant potential in a large variety of preclinical anticonvulsant models. Present review article is an attempt to compile the various central nervous system potential of synthesized isatin analogs which will serve as a valuable source of information for the researchers working in this field.

Currently, cell biology is based on glucose as the main source of energy. Cellular bioenergetic pathways have become unnecessarily complex in their eagerness to explain that how the cell is able to generate and use energy from the oxidation of glucose, where mitochondria play an important role through oxidative phosphorylation. During a descriptive study about the three leading causes of blindness in the world, the ability of melanin to transform light energy into chemical energy through the dissociation of water molecule was unraveled. Initially, during 2 or 3 years; we tried to link together our findings with the widely accepted metabolic pathways already described in metabolic pathway databases, which have been developed to collect and organize the current knowledge on metabolism scattered across a multitude of scientific articles. However, firstly, the literature on metabolism is extensive but rarely conclusive evidence is available, and secondly, one would expect these databases to contain largely the same information, but the contrary is true. For the apparently well studied metabolic process Krebs cycle, which was described as early as 1937 and is found in nearly every biology and chemistry curriculum, there is a considerable disagreement between at least five databases. Of the nearly 7000 reactions contained jointly by these five databases, only 199 are described in the same way in all the five databases. Thus to try to integrate chemical energy from melanin with the supposedly well-known bioenergetic pathways is easier said than done; and the lack of consensus about metabolic network constitutes an insurmountable barrier. After years of unsuccessful results, we finally realized that the chemical energy released through the dissociation of water molecule by melanin represents over 90% of cell energy requirements. These findings reveal a new aspect of cell biology, as glucose and ATP have biological functions related mainly to biomass and not so much with energy. Our finding about the unexpected intrinsic property of melanin to transform photon energy into chemical energy through the dissociation of water molecule, a role performed supposedly only by chlorophyll in plants, seriously questions the sacrosanct role of glucose and thereby mitochondria as the primary source of energy and power for the cells.

In last decade, the development of new drugs and drug products for central nervous system (CNS) has remained limited due to incomplete elucidation of pathophysiology of many CNS disorders, complexity of the diseases and the lack of technologies for delivery through the blood-brain barrier (BBB). In this article we will summarize the development of diazenyl derivatives of many biologically active moieties like benzodiazepine, formazan, indole, pyrimidine, thiazole, sulfonamide etc. as diagnostic and therapeutic agents for CNS. The potential of already existing azo compounds as potent CNS agents have also been discussed. This overview will provide the researchers an opportunity for further development of new diazenyl derivatives in CNS area.

BACE1, the aspartate protease that generates amyloid-β peptide (Aβ) in the brain of AD (Alzheimer’s disease) patients, has emerged as a pharmaceutically relevant target. Here, a fragment-based in silico approach has been adopted to design novel compounds with increased ligand efficiency for BACE1, before screening for brain permeability and toxicity. Fragments docked to the active site of BACE1 and sorted into two groups using binding energy cut-off, were joined to create novel ligands with binding energy lying in the range between -11.36 kcal/mol and -8.56 kcal/mol. Interestingly, QIN, a known inhibitor of BACE1 with an IC50 of 11nM, when docked to BACE1, shows a binding energy (-9.43 kcal/mol) lying within the range of the novel ligand-BACE1 complexes. The present strategy thus enabled the design of four novel inhibitors of BACE1 with favourable binding energy, brain permeability and no toxicity that might show promise as leads in future.