Search

Depression is not similar to daily mood fluctuations and temporary emotional responses to day‐to‐day activities. Depression is not a passing problem; it is an ongoing problem. It deals with different episodes consisting of several symptoms that last for at least 2 weeks. It can be seen for several weeks, months, or years. At its final stage, or can say, in its worst condition, it can lead to suicide. Antidepressants are used to inhibit the reuptake of the neurotransmitters by some selective receptors, which increase the concentration of specific neurotransmitters around the nerves in the brain. Drugs that are currently being used for the management of various types of depression include selective serotonin reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, serotonin, noradrenaline reuptake inhibitors, etc. In this review, we have outlined different symptoms, causes, and recent advancements in nitrogen‐containing heterocyclic drug candidates for the management of depression. This article highlights the various structural features along with the structure–activity relationship (SAR) of nitrogen‐containing heterocyclics that play a key role in binding at target sites for potential antidepressant action. The in silico studies were carried out to determine the binding interactions of the target ligands with the receptor site to determine the potential role of substitution patterns at core pharmacophoric features. This article will help medicinal chemists, biochemists, and other interested researchers in identifying the potential pharmacophores as lead compounds for further development of new potent antidepressants. [ABSTRACT FROM AUTHOR]

Serotoninergic signaling is identified as a crucial player in psychiatric disorders (notably depression), presenting it as a significant therapeutic target for treating such conditions. Inhibitors of serotoninergic signaling (especially selective serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRI)) are prominently selected as first-line therapy for the treatment of depression, which benefits via increasing low serotonin levels and norepinephrine by blocking serotonin/norepinephrine reuptake and thereby increasing activity. While developing newer heterocyclic scaffolds to target/modulate the serotonergic systems, imidazole-bearing pharmacophores have emerged. The imidazole-derived pharmacophore already demonstrated unique structural characteristics and an electron-rich environment, ultimately resulting in a diverse range of bioactivities. Therefore, the current manuscript discloses such a specific modification and structural activity relationship (SAR) of attempted derivatization in terms of the serotonergic efficacy of the resultant inhibitor. We also featured a landscape of imidazole-based development, focusing on SAR studies against the serotoninergic system to target depression. This study covers the recent advancements in synthetic methodologies for imidazole derivatives and the development of new molecules having antidepressant activity via modulating serotonergic systems, along with their SAR studies. The focus of the study is to provide structural insights into imidazole-based derivatives as serotonergic system modulators for the treatment of depression. [ABSTRACT FROM AUTHOR]

Pyrimidine itself or in different fused forms is an important chemical motif for every step of cell life. Alongside, it exists as a key pharmacophoric part in thiamine, alloxan, orotic acid, and other isoforms of nucleotide bases. It has emerged as a privileged scaffold in medicinal chemistry due to its various possible structural and pharmacological attributes. In a number of clinically used chemical agents, pyrimidine or its fused/clubbed form with other moieties act as a key pharmacophore. Structure activity relationship (SAR) studies of the explored derivatives demonstrated that slight modifications with various substitutions on the pyrimidine rings can deviate biological activity to a large extent. 2‐Pyrimidone and 2,4‐pyrimidione derivatives are largely explored by a number of research groups for various pharmacological targets and due to their similarity to nucleotide bases, it has a great impact on the biological profile of these molecules. The current review focuses on describing the recent advancements (2015 onward) in the development of pyrimidine‐based biologically active molecules along with drug candidates under different clinical trials. The aim of this review is to provide structural features associated with pyrimidine along with their SAR studies, which are believed to be valuable for the scientists working on the development of pyrimidine‐based small molecules in the aforementioned disease conditions. We believe that the results of this research will help to provide a structural idea that may be used in the design and development of new pyrimidine‐based small molecules that target a variety of receptors or enzymes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sodium channel inhibitors are the promising target for the management of convulsions. • Detailed pharmacology of sodium channel. • Development of anticonvulsant drugs as voltage gated sodium channel inhibitors. • Detailed pharmacological activity, SAR and possible mechanisms is discussed. Voltage-gated sodium channel blockers are one of the vital targets for the management of several central nervous system diseases, including epilepsy, chronic pain, psychiatric disorders, and spasticity. The voltage-gated sodium channels play a key role in controlling cellular excitability. This reduction in excitotoxicity is also applied to improve the symptoms of epileptic conditions. The effectiveness of antiepileptic drugs as sodium channel depends upon the reversible blocking of the spontaneous discharge without blocking its propagation. There are number of antiepileptic drug(s) which are in pipeline to flour the market to conquer abnormal neuronal excitability. They inhibit the seizures through the inhibition of complex voltage- and frequency-dependent ionic currents through sodium channels. Over the past decade, the sodium channel is one of the most explored targets to control or treat the seizure, but there has not been any game-changing discovery yet. Although there are large numbers of drugs approved for the treatment of epilepsy, however they are associated with several acute to chronic side effects. Many research groups have tirelessly worked for better therapeutic medication on this popular target to treat epileptic seizures. The review quotes briefly the developments of the approved examples of sodium channel blockers as anticonvulsant drugs. Medicinal chemists have tried the design and development of some more potent anticonvulsant drugs to minimize the toxicity that are discussed here, and an emphasis is given for their possible mechanism and the structure–activity relationship (SAR). [ABSTRACT FROM AUTHOR]

Cancer represents one of the world's biggest hazardous diseases. p53 is the uttermost researched tumour suppressor protein. It is commonly considered the "guardian of the genome," performing a critical function in genetic stability maintenance through controlling the cell cycle, programmed cell death, DNA repair, aging, and angiogenesis. The abnormalities in p53 lead to genetic instability and plays a significant role in carcinogenesis. The role of p53 in tumour suppression is emphasized in addition by the observation that primary silencing with this protein occurred in more than 50% of cancers. MDM2, p53, and the p53-MDM2 connections are well-known targets for the prevention and treatment of cancer. Moreover, in tumors with wild-type p53, their efficacy is decreased due to MDM2 enlargement or by the gradual decrease of MDM2 blocker ARF. As a result, improving p53 activity in cancerous cells provides a promising anticancer strategy. Various techniques are now being investigated, and addressing the p53-MDM2 interaction had also evolved as a potentially feasible strategy for contending with tumors. Both p53 and MDM2, interact via an autoregulation response signal: p53 activity induces MDM2 transcription, which in response interacts with p53's N-terminal transactivation domain, inhibiting its transcriptional activity. This article provides information on the current scenario of anti-tumor activities, with a particular emphasis on structure-activity relationship characteristics (SAR) against the p53-MDM2 to treat cancer. The primary purpose of this review is to cover recent advancements in the creation and testing of anticancer drugs that target the p53-MDM2 structure. This review contains different heterocyclic moieties which show significant results toward cancer. A mechanistic route is shown here, demonstrating both normal and malignant conditions via several stressed factors. Several compounds entered clinical trials as p53-MDM2 inhibitors for the treatment of cancer. [Display omitted] • p53, "guardian of the genome," abnormalities play a significant role in carcinogenesis. • p53 primary silencing is in more over 50% of cancers and potential target of cancer. • This manuscript emphasis on SAR against the p53-MDM2 to treat cancer. • It covers recent advancements in the creation and testing of anticancer drugs targeting p53-MDM2. [ABSTRACT FROM AUTHOR]

Gamma-Aminobutyric Acid (GABA) inhibitory neurotransmitter departs an energetic role in brain signalling system. Levels of GABA in the brain influence human behaviour, diminishes in the degree of GABA can cause seizures, depression, Parkinson's. To put it plainly, it plays a basic part in the significant issues of mind. It is exceptionally important to cure the issues linked to GABA. Writing overview proposed that nipecotic acid is an intense GABA reuptake inhibitor. This scaffold is likewise present in one of the promoted anticonvulsant drugs 'Tiagabine'. Tiagabine is only drug in the market which works through this mechanism however the medication is regulated with one more prescription for the synergistic impact. Nipecotic acid has several disadvantages such as it can't cross the blood-brain barrier because of its hydrophilic and zwitterionic nature. To avoid this problem nipecotic acid scaffold hybrids with the different aromatic groups can enhance the physical (lipophilicity) as well as biological properties of the resultant compound. So, there is a dire requirement for compounds that work through this mechanism. Several medicinal chemists and researchers are already working in this field and developed outstanding newer molecules. This review article compiles these developed new hybrids along with design strategies, structure-activity relationship, and biological activity as well as in silico studies. This review also demonstrates the synthesis of nipecotic acid and the core mechanism through which nipecotic acid acts as a GABA reuptake inhibitor. [Display omitted] • Hybrids of Nipecotic acid emerged as potential drug candidates. • In recent years target selectivity is in great focus for the development of selective inhibitors. • The GABA reuptake inhibition of the synthesized potent derivatives was discussed along with their SAR. • The review focused on biological activity, SAR and in silico studies of developed GABA reuptake inhibitors. [ABSTRACT FROM AUTHOR]

• Recent developments of nitrogen-containing heterocyclic compounds as antidepressant have been discussed. • The antidepressant profile of the potent derivatives along with structural insights is presented. • The SAR studies of recently developed compounds are discussed in details for providing key structural features. • The lead compounds for further development are identified and discussed in the perspective part of this review. According to the World Health Organization (WHO), depression is a common mental disorder and includes complex interaction between social and psychological behaviour affecting 264 million people worldwide. The review aims to highlight the role and importance of nitrogen-based heterocyclics in the development of antidepressant compounds. Many research groups have attempted to design drug candidates capable of binding within the receptors. The commonest drug design strategy includes the incorporation of different structural features widely recognized as an antidepressant in the synthesized derivatives to enhance their CNS antidepressant effects. In this review, we have shed light on nitrogenous heterocyclic moieties such as quinazoline, pyridine, pyrimidine, pyrrolidine, imidazole, pyrazole, piperidine, oxadiazole, benzimidazole, benzothiazole, piperazine, triazine, purine, benzoxazole, and isoxazole as core nucleus and/or in combination as an antidepressant compound. These molecules with different structural features were noted to exert their antidepressant effects by multiple mechanisms viz., selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, and Catechol- O -methyltransferase (COMT) inhibitors. The review focuses on the selection of these heterocyclic moieties for the further design and development of promising antidepressants by taking a clue from the earlier reported potent antidepressant compounds or from the marketed products. The results have been correlated with their structural activity relationship (SAR) to identify the substituents for the potency and selectivity within the receptors. This review might help the researchers working in the antidepressant field to develop more novel molecules that could fill the gap by improving potency and reducing toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Pyrazolines remain privileged heterocycles in drug discovery. 2-Pyrazoline scaffold has been proven as a ubiquitous motif which is present in a number of pharmacologically important drug molecules such as antipyrine, ramifenazone, ibipinabant, axitinib etc. They have been widely explored by the scientific community and are reported to possess wide spectrum of biological activities. For combating unprecedented diseases and worldwide increasing drug resistance, 2-pyrazoline has been tackled as a fascinating pharmacophore to generate new molecules with improved potency and lesser toxicity along with desired pharmacokinetic profile. This review aims to summarizes various recent advancements in the medicinal chemistry of pyrazoline based compounds with the following objectives: (1) To represent inclusive data on pyrazoline based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical developments; (2) To discuss recent advances in the medicinal chemistry of pyrazoline derivatives with their numerous biological significances for the eradication of various diseases; (3) Summarizes structure-activity relationships (SAR) including in silico and mechanistic studies to afford ideas for the design and development of novel compounds with desired therapeutic implications. Image 1 • Pyrazoline is considered as an interesting scaffold with diverse array of pharmacological properties. • Recent advances in numerous therapeutic implications of pyrazoline derivatives have been described in this article. • The review provides a deep insight regarding in vitro and in vivo pharmacological activities of pyrazolines. • Their SAR, in silico and mechanistic studies has also been described in the manuscript. • The article provides enormous idea to explore therapeutic potentials of new pyrazoline motifs. [ABSTRACT FROM AUTHOR]