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Cancer is a growing problem that has not yet been fully harnessed. Frequent mutations make this a highly variable and challenging pathology. Interestingly, mitochondria have currently emerged as a new target for cancer therapy. A group of agents with anticancer activity, termed mitocans that encourage apoptosis through mitochondrial disruption is currently important in research. From conventional glycolytic inhibitors to recent radiolabeled compounds, mitochondrial‐targeted therapies have marked their presence in cancer. Several TCA cycle and OXPHOS inhibitors are being established for their possible anticancer properties. There are so many distinctive differences in mitochondrial structure and function between normal and cancer cells that offer the potential for the clinical use of mitochondria as targets for novel and site‐specific anticancer agents. Mitochondrial targeting can be made possible if the bioactive molecule is specifically and selectively delivered to the mitochondria of the correct cell type using cell‐specific ligands and mitochondriotropic molecules. [ABSTRACT FROM AUTHOR]

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]

An Indian traditional medicinal plant, Boerhaavia diffusa (Punarnava), is reported for its diuretic activity and helps in impaired kidney function. The present study indicates that alkaloids, carbohydrates, saponins, phytosterols, flavonoids, and glycosides are absent in the petroleum ether extract and present chiefly in the methanolic extract of roots. The phytosterols were found to be present in the ethyl acetate extract, while other phytochemical constituents, that is, alkaloids, carbohydrates, saponins, flavonoids, and glycosides, were absent. From high‐performance thin‐layer chromatography, the results indicated that out of all the three extracts and two marketed formulations, ethyl acetate root extract (LEA) has the highest amount of Boeravinone B content. Further, different root extracts of B. diffusa and two marketed formulations were evaluated on the human embryonic kidney cell line to understand pharmacological safety. From the results, it was observed that LEA and petroleum ether root extracts showed a higher percentage of cell survival and a better safety profile up to the dose of 1 mg/mL. The overall results indicated that further preclinical evaluation of B. diffusa is needed to understand the mechanism behind nephroprotective potential which can further expedite the drug discovery process of nephroprotective molecules. [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]

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized. [ABSTRACT FROM AUTHOR]

1-Substituted 1,2,4-triazole derivatives present in a large number of compounds and display a variety of bioactivities such as antibiotic, anti-inflammatory, anti-diabetic, antipsychotic, and anticancer. A regioselective protocol has been developed for the alkylation of 1,2,4- triazole using mild conditions. The 1-alkyl-1,2,4-triazole derivatives were synthesized under microwave conditions using potassium carbonate as a base and ionic liquid (hexylpyridinium bromide) as a solvent. The products were obtained in excellent yield, and the base-ionic liquid combination was recycled for a number of times.

A series of isatin-based fused heterocycles were designed, synthesized, and evaluated for anticancer activity against four cancer cell lines: MCF-7, MDA-MB-231, A549, and HL-60. Among them, Q3 and T4 were found to be potent anticancer agents. Furthermore, two compounds Q3 and T4 were selected for epidermal growth factor receptor (EGFR) inhibitory activity. Two compounds Q3 and T4 were found to be most potent EGFR inhibitors with IC50 of 0.22 ± 0.10 and 0.19 ± 0.07 μM. The EGFR inhibitory activity of standard drug erlotinib was 0.08 ± 0.02 μM. Structural Activity Relationship studies showed that electronegative atoms were necessary for EGFR inhibitory potential. Finally, molecular docking studies were carried out to check the binding pattern of synthesized derivatives with the adenosine triphosphate (ATP) binding site of EGFR and results revealed that compounds Q3 (−9.2 kcal/mol) and T4 (−8.9 kcal/mol) exhibited better binding affinity than reference drug erlotinib (−7.3 kcal/mol). [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]

The severity and prevalence of cancer in modern time are a huge global health burden. Continuous efforts are being made toward the development of newer therapeutic candidates to treat and manage this ailment. The dihydropyrimidinone scaffold is one of the key nuclei that have been highly explored and investigated against cancer. It has the potential to combat the consequences of cancer by interacting with several biological targets. Tubulin polymerization inhibition is one such strategy to prevent the progression of cancer. In the presented work, we have synthesized a series of sixteen dihydropyrimidinone derivatives by following a rational drug design. The synthesized compounds have been characterized by 1H NMR and 13C NMR and were further evaluated for cytotoxic activity against breast cancer cell lines (MCF-7 and MDA-MB-231), lung cancer cell lines (A549), and colon cancer cell lines (HCT-116). Compounds 5D and 5P were found most potent and revealed a better cytotoxic activity compared with the standard drug colchicine. Furthermore, the tubulin polymerization inhibition assay revealed that compound 5D showed better inhibition than colchicines, whereas compound 5P revealed an almost equal inhibition to that of colchicine. Furthermore, to investigate the possible mode of action and binding patterns, compounds 5P and 5D were subjected to molecular docking against tubulin (Protein Data Bank ID: ISA0). The results showed that compounds revealed significant interactions and were well occupied inside the cavity of tubulin. The compounds 5D and 5P may serve as new leads in drug development against cancer. [ABSTRACT FROM AUTHOR]

The current anti‐inflammatory drugs are associated with various severe adverse or side effects which mark the question on long term clinical use of such medications. These factors necessitate the development of new heterocyclic molecules having anti‐inflammatory potential with minimal to no adverse effect or toxicity. In continuation to our work, in herein report design and synthesis of a series of 15 indole‐3‐subtituted isoxazoles having potential anti‐inflammatory as well as analgesic properties. Most of the compounds exhibited comparable in‐vivo anti‐inflammatory and analgesic activity in rats to the reference drugs. Compound 9 d, 9 f and 9 i were found to show most significant anti‐inflammatory activity and reduced the paw edema by 67.74 %, 61.29 %, and 77.42 % respectively which were comparable to reference drug indomethacin. The COX inhibition studies reveled that these compounds have 2–3 folds selectivity for COX‐2 with moderate inhibition activity. In final, molecular docking studies were performed to understand the mechanistic and binding modes at catalytic active sites of COX‐2. The results revealed good selectivity of compounds for COX‐2 preferably over other inflammatory targets. The compound 9 i is obtained as lead molecule from the current series as promising structural feature for further development of novel anti‐inflammatory agent. [ABSTRACT FROM AUTHOR]

Depression is declared the second leading cause of disability worldwide. Recently, cases of depression have increased significantly in adolescents, young adults as well as in elder population. Monoamine oxidase‐A (MAO‐A) is considered one of the major targets for the treatment of depression. In the current study, we have designed and synthesized various indole functionalized piperazinyl derivatives and evaluated them for in vitro MAO‐A inhibitory activity and in vivo antidepressant‐like activity. Most of the compounds were found to possess potent MAO‐A inhibitory activity with IC50 values in the sub‐micromolar range along with significant selectivity over MAO‐B. Compounds RP1 and RP9 emerged as the most promising reversible MAO‐A inhibitors with IC50 values of 0.11±0.03 μM and 0.14±0.02 μM and displayed selectivity of 193 folds and 178 folds over Monoamine oxidase‐B (MAO‐B), respectively. In the series, RP1 showed good intracellular ROS inhibitory activity along with neuroprotective properties. These compounds were found nontoxic against SH‐SY5Y cells and explored antidepressant activities. In the in vivo Forced swimming test (FST) and Tail suspension test (TST) studies, RP1 exhibited potential antidepressant‐like behavior similar to standard drug fluoxetine while compound RP9 showed antidepressant‐like activity only in the TST studies. The molecular docking and dynamics studies further supported the results obtained in the in vitro and in vivo studies. Thus, the indole functionalized piperazinyl derivatives were found to be promising ligands and can be developed as new antidepressant molecules. [ABSTRACT FROM AUTHOR]