Recent Advancement in Drug Design and Discovery of Pyrazole Biomolecules as Cancer and Inflammation Therapeutics.

Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC50, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.

3'-(4-(Benzyloxy)phenyl)-1'-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies.

Pyrazoline-linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF-7 (breast cancer), A549 (non-small-cell lung tumor), HCT-116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC50 values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4',6-diamidino-2-phenylindole (DAPI) staining and phase-contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence-activated cell sorting using Annexin V-FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate-binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non-small-cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.

Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008-2019).

Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008-2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores.

Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives.

A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARγ receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m &6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARγ transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARγ modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARγ gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver.

Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure-Activity Relationship.

Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body. Benzimidazole is an organic compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 8.8 million deaths of which 70% of the cases were from low- and middle-income countries. In the efforts to develop suitable anticancer drugs, medicinal chemists have focussed on benzimidazole derivatives. This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure-activity relationships (SAR).

Design, Synthesis, Molecular Docking, and Anticancer Evaluation of Pyrazole Linked Pyrazoline Derivatives with Carbothioamide Tail as EGFR Kinase Inhibitors.

BACKGROUND: The Epidermal Growth Factor Receptor (known as EGFR) induces cell differentiation and proliferation upon activation through the binding of its ligands. Since EGFR is thought to be involved in the development of cancer, the identification of new target inhibitors is the most viable approach, which recently gained momentum as a potential anticancer therapy. OBJECTIVE: To assess various pyrazole linked pyrazoline derivatives with carbothioamide for EGFR kinase inhibitory as well as anti-proliferative activity against human cancer cell lines viz. A549 (non-small cell lung tumor), MCF-7 (breast cancer cell line), SiHa (cancerous tissues of the cervix uteri), and HCT-116 (colon cancer cell line). METHODS: In vitro EGFR kinase assay, in vitro MTT assay, Lactate dehydrogenase release, nuclear staining (DAPI), and flow cytometry cell analysis. RESULTS: Compounds 6h and 6j inhibited EGFR kinase at concentrations of 1.66µM and 1.9µM, respectively. Furthermore, compounds 6h and 6j showed the most potent anti-proliferative results against the A549 KRAS mutation cell line (IC50 = 9.3 & 10.2µM). Through DAPI staining and phase contrast microscopy, it was established that compounds 6h and 6j also induced apoptotic activity in A549 cells. This activity was further confirmed by FACS using Annexin-V-FITC and Propidium Iodide (PI) labeling. Molecular docking studies performed on 6h and 6j suggested that the compounds can bind to the hinge region of ATP binding site of EGFR tyrosine kinase in a similar pose as that of the standard drug gefitinib. CONCLUSION: The potential anticancer activity of compounds 6h and 6j was confirmed and need further exploration in cancer cell lines of different tissue origin and signaling pathways, as well as in animal models of cancer development.

Recent advancement in the discovery and development of anti-epileptic biomolecules: An insight into structure activity relationship and Docking.

Although there have been many advancements in scientific research and development, the cause of epilepsy still remains an open challenge. In spite of high throughput research in the field of anti-epileptic drugs, efficacy void is still prevalent before the researchers. Researchers have persistently been exploring all the possibilities to curb undesirable side effects of the anti-epileptic drugs or looking for a more substantial approach to diminish or cure epilepsy. The drug development has shown a hope to medicinal chemists and researchers to carry further research by going through a substantial literature survey. This review article attempts to describe the recent developments in the anti-epileptic agents, pertaining to different molecular scaffolds considering their structure-activity relationship, docking studies and their mechanism of actions.

Genomic and Functional Characterization of Enterococcus mundtii QAUEM2808, Isolated From Artisanal Fermented Milk Product Dahi.

Microbial strains with a unique combination of technological and bioactive properties are preferred for industrial applications. The present study was conducted to evaluate the potential use of Enterococcus mundtii QAUEM2808 (NCBI Accession Number: LSMC00000000) in milk fermentation. This strain was isolated from Dahi, an indigenous fermented milk product of South-East Asia. The in vitro study confirmed the acidification ability as well as the proteolytic, cellulolytic, and amylolytic enzyme activities of this strain. It also produced a substantial amount of the folate in laboratory media and no physiological dysfunctions in laboratory animals was observed in feeding trials. All these properties were confirmed by in silico genome analysis. The Enterococcus mundtii QAUEM2808 genome consisted of a single, circular chromosome comprising 2,957,300-bp, 2,587 genes with GC content of 38.5%. Moreover, 16t RNAs, 1, 3 (16S, 23S) rRNAs, 4 ncRNAs, and 91 pseudo genes were also predicted. The majority of genome encode genes for protein, amino acids, carbohydrate, cell wall DNA and RNA metabolisms including all genes required for conversion of lactose to lactic acid. It also exhibited antimicrobial activity against E. coli ATCC 10536, S. aureus ATCC 6538, P. aeruginosa ATCC 9027, and L. monocytogenes ATCC 13932 and was found to be sensitive to commonly used antibiotics. The in silico analysis revealed the presence of genes for mundaticin and enterocin production, and CRISPER regions, however, the genes for antibiotic resistance were absent. No genes related to the pathogenicity island and prophages were detected by genome mining. Therefore, it could be inferened that Enterococcus mundtii QAUEM2808 has the potential to be used in milk fermentation as adjunct culture.

Recent advancement of piperidine moiety in treatment of cancer- A review.

Piperidine is an important pharmacophore, a privileged scaffold and an excellent heterocyclic system in the field of drug discovery which provides numerous opportunities in studying/exploring this moiety as an anticancer agent by acting on various receptors of utmost importance. Cancer is an uncontrolled division of cells that results in the formation of tumour which have the potential to migrate to other parts of the body (metastasis) finally becoming a major threat to human population. Since piperidine displayed great potential in this area it is being further probed to get novel entities for the treatment of cancer. This review throws light on recent biological expansions of piperidine along with structure activity relationships to deliver association between various synthesized newer/novel derivatives and receptor sites.

Therapeutic journey of 2,4-thiazolidinediones as a versatile scaffold: An insight into structure activity relationship.

Thiazolidinedione is an important heterocyclic ring system, a pharmacophore and a privileged scaffold in medicinal chemistry; is a derivative of thiazolidine ring which came into existence for its role as antihyperglycemic agent and a specific ligand of PPAR's (Peroxisome proliferator activated receptor). Exhaustive research has led to determination of its vast biological profile with wide range of therapeutic applications. This review covers recent pharmacological advancements of thiazolidinedione moiety along with structure activity relationship so as to provide better correlation among different structures and their receptor interactions.

Current status of pyrazole and its biological activities.

Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy.