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.

Lipid-based nanoformulations in the treatment of neurological disorders.

The neurological disorders affect millions of people worldwide, and are bracketed as the foremost basis of disability-adjusted life years (DALYs). The treatment options are symptomatic and often the movement of drugs is restricted by a specialized network of endothelial cell layers (adjoined by tight cell-to-cell junction proteins; occludin, claudins, and junctional adhesion molecules), pericytes and astroglial foot processes. In recent years, advances in nanomedicine have led to therapies that target central nervous system (CNS) pathobiology via altering signaling mechanisms such as activation of PI3K/Akt pathway in ischemic stroke arrests apoptosis, interruption of α-synuclein aggregation prevents neuronal degeneration in Parkinson's. Often such interactions are limited by insufficient concentrations of drugs reaching neuronal tissues and/or insufficient residence time of drug/s with the receptor. Hence, lipid nanoformulations, SLNs (solid lipid nanoparticles) and NLCs (nanostructured lipid carriers) emerged to overcome these challenges by utilizing physiological transport mechanisms across blood-brain barrier, such as drug-loaded SLN/NLCs adsorb apolipoproteins from the systemic circulation and are taken up by endothelial cells via low-density lipoprotein (LDL)-receptor mediated endocytosis and subsequently unload drugs at target site (neuronal tissue), which imparts selectivity, target ability, and reduction in toxicity. This paper reviews the utilization of SLN/NLCs as carriers for targeted delivery of novel CNS drugs to improve the clinical course of neurological disorders, placing some additional discussion on the metabolism of lipid-based formulations.

Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents.

We herein report the design, synthesis and molecular docking studies of 2,4-thiazolidinedione derivatives containing benzene sulphonyl group which are docked against the Peroxisome Proliferator Activated Receptor (PPARγ) target. Compound 7p was most effective in lowering the blood glucose level as compared to standard drugs pioglitazone and rosiglitazone. Compound 7p exhibited potent PPAR-γ transactivation of 61.2% with 1.9 folds increase in gene expression. In molecular docking studies 7p showed excellent interactions with amino acids TYR 473, SER 289, HIE 449, TYR 327, ARG 288, MET 329 and LEU 228. Compound 7p did not cause any damage to the liver without any noteworthy weight gain and may be considered as promising candidates for the development of new antidiabetic agents.

Design, synthesis, and molecular docking study of benzothiazolotriazine derivatives for anticonvulsant potential.

A series of newer benzothiazolotriazine derivatives (4a-k) was designed, synthesized, and characterized as anticonvulsant agents against the two classically used MES and scPTZ animal models. The synthesized derivatives were tested in vivo in both the animal models, followed by a neurotoxicity study by the rotarod method. Compound 4e, 8-chloro-4-(2-chlorocyclohexa-1,5-dien-1-yl)-2-((4-methoxybenzyl)thio)-10aH-benzo[4,5]thiazolo[3,2a][1,3,5]triazine was found most promising among the series in both the animal models, with no neurotoxicity. From this it may be confirmed that the presence of a methoxy (OCH3 ) group at the lipophilic aryl ring was showing high anticonvulsant potency. In the molecular modeling study, compound 4e (docking score = -8.70) showed important hydrogen bond interaction with the amino acids LYS 329, SER 137, GLY 136 and π-π interactions with PHE 189 at the active site of GABA-AT. These derivatives can be further explored for the development of newer/novel anticonvulsant agents.

Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole-based 2,4-thiazolidinedione derivatives as PPAR-γ modulators.

The design, synthesis, structure-activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-γ by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > -8 as compared to the standard drug, rosiglitazone (Glide XP score = -9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR-γ transactivation and in vivo blood glucose lowering activity in the streptozotocin-induced diabetic rat model. Compounds 5o, 5n, 5a, 5i, and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR-γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o, 5n, and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR-γ gene expression by 2.35-fold as compared to rosiglitazone (1.27-fold) and pioglitazone (1.6-fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver.

Design, synthesis, anticonvulsant evaluation and docking study of 2-[(6-substituted benzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothioureas.

In this paper, we report the synthesis of 2-[(6-substituted benzo[d]thiazol-2-ylcarbamoyl)methyl]-1-(4-substituted phenyl)isothiourea derivatives (4a-y) carrying active pharmacophores essential for anticonvulsant activity. The anticonvulsant activity was evaluated in vivo by maximal electroshock (MES) test and subcutaneous pentylenetetrazole (scPTZ) test in mice. Most of the compounds showed promising anticonvulsant activity. The most active compounds 4b and 4q were found active in both MES and scPTZ models, without signs of neurotoxicity. Compound 4b showed the moderate change in SGOT and alkaline phosphatase level as compared to control. Compounds 4b and 4w were also found to elevate GABA levels in the olfactory lobe, mid brain, medulla oblongata and cerebellum regions of rat brain. In molecular docking study, the title compounds exhibited good binding properties with epilepsy molecular targets such as GABA-A. Structure-activity relationships are also elaborated along with the analysis of lipophilicity. The results suggested that compound 4b is likely to have varied mechanisms of action including voltage-gated ion channel inhibition and modulating GABAergic action.

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, and Docking Study of Pyrimidine-Triazine Hybrids for GABA Estimation in Animal Epilepsy Models.

A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED50 ), 285.02 and 293.42 mg/kg (scPTZ ED50 ), and 389.11 and 412.16 mg/kg (TD50 ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABAA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.

An Updated and Focused Review on Heterocyclic Inhibitors for SARSCoV and SARS-CoV-2 3CLpro.

BACKGROUND: SARS-CoV and SARS-CoV-2 are exceedingly contagious and typically result in major respiratory illnesses (acute respiratory syndrome). The public health is facing enormous challenges across all the nations due to these newly emerging pathogens. Reliable and systematic examination of SARS-CoV and COVID-19 will assist in identifying infectious persons accurately. Based on the biological, chemical, and genetic link of SARS CoV-2 towards SARS-CoV, the recurrence of different anti-SARS-CoV natural drug molecules may be beneficial in the advancement of anti-COVID-19 herbal drug molecules. Here in this review, we evaluated SAR research that has recently been published as well as molecular docking analysis of previously synthesised compounds that have been targeted against SARS-CoV and SARS-CoV-2, respectively. This investigation might assist scientists in creating novel and revolutionary molecules that could target SAR-CoV-2. OBJECTIVES: The review highlights the heterocyclic inhibitors' ability to successfully inhibit SARSCoV and SARS-CoV-2. The meticulously described structure-activity relationship of potential SARS-CoV and SARS-CoV-2 inhibiting compounds has been addressed in this review. EVIDENCE ACQUISITION: We conducted a thorough literature assessment employing electronic databases for scientific articles highlighting potential heterocyclic inhibitors for SARS-CoVand SARSCoV- 2, published from 2010 to 2021. We recovered 415 articles, but only 220 were involved and conversed in this manuscript. The article apprehended appropriate research considering three areas: 1) SAR activity, 2) Molecular docking, and 3) Biological activity and future prospects on SARS-CoV-2. METHODS: The potential compounds with decent inhibitory activity have been discussed and reviewed along with their inhibition potential, expressed in terms of IC50 value. RESULTS: Heterocyclic scaffolds reflect an extensive spectrum of therapeutic activity and might function as an initiating concept for the designing and discovery of potential inhibitors for SARS-CoV and SARS-CoV-2 treatment. CONCLUSION: The points highlighted here may prove to be a vital tool for medicinal chemists working/ investigating more potent and efficacious scaffolds in treating SARS-CoV and SARS-CoV-2.

Overview of Chemistry and Therapeutic Potential of Non-Nitrogen Heterocyclics as Anticonvulsant Agents.

Epilepsy is a chronic neurological disorder, characterized by the predisposition of unprovoked seizures affecting the neurobiological, psychological, cognitive, economic, and social wellbeing of the patient. As per the 2019 report by World Health Organization, it affects nearly 80% of the population, which comes from middle to low-income countries. It has been suggested that 70% of such cases can be treated effectively if properly diagnosed. It is one of the most common neurological diseases affecting 50 million people globally. Most of the antiepileptic drugs used in clinical practice are only 60-80% effective in controlling the disease. These drugs suffer from serious drawbacks of non-selectivity and toxicity that limit their clinical usefulness. Hence, there is a need to search for safe, potent, and effective anti-epileptic drugs. One of the emerging strategies to discover and develop selective and non-toxic anticonvulsant molecules focuses on the design of non-nitrogen heterocyclic compounds (NNHC). Drugs such as valproic acid, gabapentin, viagabatrin, fluorofelbamate, tiagabine, progabide, pregabalin, gamma amino butyric acid (GABA), etc. do not contain a nitrogen heterocyclic ring but are as effective anticonvulsants as conventional heterocyclic nitrogen compounds. This review covers the various classes of NNHC which have been developed in the recent past as anticonvulsants along with their chemistry, percentage yield, structure-activity relationship and biological activity. The most potent compound in each series has been identified for comparative studies, for further structural modification and to improve the pharmacokinetic profile. Various optimized synthetic pathways and diverse functionalities other than nitrogen-containing rings discussed in the article may help medicinal chemists to design safe and effective anticonvulsant drugs in near future.

Recent Advancements in CNS Acting Drugs: A Step Towards End of Illness.

Progressive degeneration in the morphology and functions of neuronal cells leads to multifactorial pathogenesis conditions of oxidative stress, mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and neuro-inflammation to mediate heterogeneous types of neurodegenerative diseases, such as Epilepsy, Alzheimer's (AD) and Parkinson's (PD), more prominently among aging populations. In this editorial, complex mechanisms, challenges, and advancements made in the discovery of new neurotherapeutics, as well as designing approaches being adopted to fabricate brain-targeted delivery systems, are discussed.

Design, Synthesis, Molecular Docking, and Biological Evaluation of Pyrazole Hybrid Chalcone Conjugates as Potential Anticancer Agents and Tubulin Polymerization Inhibitors.

Some (E)-3-(3-(4-(benzyloxy)phenyl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-one conjugates 5a-r were designed; synthesized; characterized by 1H, 13C NMR, and ESI-MS; and evaluated for tubulin polymerization inhibitory activity and in vitro cytotoxicity against breast (MCF-7), cervical (SiHa), and prostate (PC-3) cancer cell lines, as well as a normal cell line (HEK-293T). The compounds were also tested to determine their binding modes at the colchicine-binding site of tubulin protein (PDB ID-3E22), for in silico ADME prediction, for bioactivity study, and for PASS prediction studies. Among all the synthesized conjugates, compound 5o exhibited excellent cytotoxicity with an IC50 value of 2.13 ± 0.80 µM (MCF-7), 4.34 ± 0.98 µM (SiHa), and 4.46 ± 0.53 µM (PC-3) against cancer cell lines. The compound did not exhibit significant toxicity to the HEK cells. Results of the in silico prediction revealed that the majority of the conjugates possessed drug-like properties.

How Internet Websites Portray Herbal Vitality Products Containing Eurycoma longifolia Jack: An Evaluation of the Quality and Risks of Online Information.

BACKGROUND: Tongkat Ali (TA) or Eurycoma longifolia is a herbal medicine (HM) plant traditionally used to treat sexual dysfunction and enhance libido in men. Websites containing information about HM are abundant. However, studies have shown that in general the quality of websites containing information on HM is low. The present study aims to assess the quality and risks of websites containing information about TA supplements and to identify the health claims for TA. METHODOLOGY: A cross-sectional study to evaluate the quality and risks of websites discussing TA supplements was conducted. Online marketing websites, research articles, news articles, personal opinions, and those restricted by password were excluded. The quality and risks of websites were assessed using a modified DISCERN tool and a set of risk assessment criteria, respectively. The health claims for TA were identified and analyzed using content analysis. RESULTS: Overall, 321 websites met the inclusion criteria and were further evaluated. The overall rating of the quality of the websites was low, with a mean score ± standard deviation of 1.07 ± 0.51. Most websites lacked information that there may be more than one possible treatment choice and did not discuss areas of uncertainty. However, 67.9% (218/321) of the websites received a risk score of zero. A minority of websites (5/321, 1.6%) discouraged the use of conventional medicines. The most common health claims for TA included in the websites related to the enhancement of testosterone level (121/321, 37.7%), treatment of malaria (112/321, 34.9%), and improvement in libido (108/321, 33.6%). CONCLUSIONS: Websites containing information about TA supplements generally have a low-quality rating based on a modified DISCERN tool despite having a low-risk score. Government agencies and healthcare professionals (HCPs) must be more proactive in the critique and dissemination of information relating to HM, and in ensuring the safe use of HM among the public and patients.

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.

Current Status of Novel Pyridine Fused Derivatives as Anticancer Agents: An Insight into Future Perspectives and Structure Activity Relationship (SAR).

Cancer is a heterogeneous disease characterized by an abnormal and uncontrolled division of the cells leading to tumors that invade the adjacent normal tissues. After cardiovascular diseases, it is the second most prevalent disease accounting for one in every six deaths worldwide. This alarming rate thus, demands an urgent need to investigate more effective drugs to combat the said disease. Oxygen and nitrogen-based heterocyclic compounds have shown remarkable therapeutic activity towards several diseases, including cancer. In this review, we have attempted to summarize the work done in the last decade (2009-2019), highlighting the anticancer activity of pyrido fused fivemembered heterocyclic ring derivatives. Additionally, we have focused on seven heterocyclic pyridine fused rings: Imidazopyridine, Triazolopyridine, Pyrrolopyridine, Pyrazolopyridines, Thienopyridine, and Isoxazolopyridine. A total of forty-nine compounds have been studied based on their invitro cytotoxic activity and their structure-activity relationship, underlining the anticancer activity of their various pharmacophores and substituents. This review, therefore, aims to draw the attention of the researchers worldwide towards the enormous scope of development of heterocyclic drug compounds, focussing mainly on pyrido fused five-membered heterocyclic rings as anticancer drugs.

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.

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.

Pyrrole: An insight into recent pharmacological advances with structure activity relationship.

Pyrrole is a heterocyclic ring template with multiple pharmacophores that provides a way for the generation of library of enormous lead molecules. Owing to its vast pharmacological profile, pyrrole and its analogues have drawn much attention of the researchers/chemists round the globe to be explored exhaustively for the benefit of mankind. This review focusses on recent advancements; pertaining to pyrrole scaffold, discussing various aspects of structure activity relationship and its bioactivities.

Current Progress in Synthesis, Characterization and Applications of Silver Nanoparticles: Precepts and Prospects.

BACKGROUND: Silver nanoparticles (AgNPs), are amongst the utmost striking nanosized materials that are extensively applied in a variety of biomedical applications which includes diagnostic use, disease management, medical device coating, drug delivery and for personal health care. DISCUSSION: With the growing interest and its application in the health care sector, it is becoming necessary for a better understanding and exploration of AgNPs mechanism of action like biological interaction, their possible toxicity, and safety concern to human exposure. AgNPs have been the subject of researchers attention and interest due to the unique properties and quality such as shape and size depending optical, electrical, and antimicrobial potentials (antibacterial, antifungal, antiviral etc.). In recent times, several studies have been conducted on AgNPs antimicrobial potential and also a number of patents related to its synthesis, clinical role and importance have also been registered. In this review, a short overview of AgNPs synthesis approach is presented (physical, chemical, and biological or green synthesis) and it also delivers a historical outlook of AgNPs application as an antimicrobial agent which includes combined evidence of microbial resistance and safety issues with human exposure.