In-vitro antiviral activity and in-silico targeted study of quinoline-3-carboxylate derivatives against SARS-Cov-2 isolate.

In recent years, the viral outbreak named COVID-19 showed that infectious diseases have a huge impact on both global health and the financial and economic sectors. The lack of efficacious antiviral drugs worsened the health problem. Based on our previous experience, we investigated in vitro and in silico a series of quinoline-3-carboxylate derivatives against a SARS-CoV-2 isolate. In the present study, the in-vitro antiviral activity of a series of quinoline-3-carboxylate compounds and the in silico target-based molecular dynamics (MD) and metabolic studies are reported. The compounds' activity against SARS-CoV-2 was evaluated using plaque assay and RT-qPCR. Moreover, from the docking scores, it appears that the most active compounds (1j and 1o) exhibit stronger binding affinity to the primary viral protease (NSP5) and the exoribonuclease domain of non structural protein 14 (NSP14). Additionally, the in-silico metabolic analysis of 1j and 1o defines CYP2C9 and CYP3A4 as the major P450 enzymes involved in their metabolism.

An 'eFP-Seq Browser' for visualizing and exploring RNA sequencing data.

Improvements in next-generation sequencing technologies have resulted in dramatically reduced sequencing costs. This has led to an explosion of '-seq'-based methods, of which RNA sequencing (RNA-seq) for generating transcriptomic data is the most popular. By analysing global patterns of gene expression in organs/tissues/cells of interest or in response to chemical or environmental perturbations, researchers can better understand an organism's biology. Tools designed to work with large RNA-seq data sets enable analyses and visualizations to help generate hypotheses about a gene's function. We present here a user-friendly RNA-seq data exploration tool, called the 'eFP-Seq Browser', that shows the read map coverage of a gene of interest in each of the samples along with 'electronic fluorescent pictographic' (eFP) images that serve as visual representations of expression levels. The tool also summarizes the details of each RNA-seq experiment, providing links to archival databases and publications. It automatically computes the reads per kilobase per million reads mapped expression-level summaries and point biserial correlation scores to sort the samples based on a gene's expression level or by how dissimilar the read map profile is from a gene splice variant, to quickly identify samples with the strongest expression level or where alternative splicing might be occurring. Links to the Integrated Genome Browser desktop visualization tool allow researchers to visualize and explore the details of RNA-seq alignments summarized in eFP-Seq Browser as coverage graphs. We present four cases of use of the eFP-Seq Browser for ABI3, SR34, SR45a and U2AF65B, where we examine expression levels and identify alternative splicing. The URL for the browser is https://bar.utoronto.ca/eFP-Seq_Browser/. OPEN RESEARCH BADGES: This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. Tool is at https://bar.utoronto.ca/eFP-Seq_Browser/; RNA-seq data at https://s3.amazonaws.com/iplant-cdn/iplant/home/araport/rnaseq_bam/ and https://s3.amazonaws.com/iplant-cdn/iplant/home/araport/rnaseq_bam/Klepikova/. Code is available at https://github.com/BioAnalyticResource/eFP-Seq-Browser.

A journey of celecoxib from pain to cancer.

The most enthralling and versatile class of drugs called the Non-steroidal anti-inflammatory (NSAIDs) showed its therapeutic utility in inflammation, beginning from the era of classic drug 'Aspirin'. NSAIDs and their well-established action based on inhibiting the COX-1 and COX-2 enzyme leads to blockage of prostaglandin pathway. They further categorized into first generation (non-selective inhibitor) and second generation (selective COX-2 inhibitors). Selective COX-2 inhibitors has advantage over non-selective in terms of their improved safety profile of gastro-intestinal tract. Rejuvenating and recent avenues for COXIBS (selective COX-2 inhibitors) explains its integrated role in identification of biochemical pain signaling as well as its pivotal key role in cancer chemotherapy. A key role player in this class is the Celecoxib (only FDA approved COXIB) a member of Biopharmaceutical classification system (BCS) II. Low solubility and bioavailability issues related with celecoxib lead to the development and advancement in the discovery and research of some possible formulation administered either orally, topically or via transdermal route. This review article intent to draw the bead on Celecoxib and it clearly explain extensive knowledge of its disposition profile, its dynamic role in cancer at cellular level and cardiovascular risk assessment. Some of the possible formulations approaches with celecoxib and its improvement aspects are also briefly discussed.

Spirulina Unveiled: A Comprehensive Review on Biotechnological Innovations, Nutritional Proficiency, and Clinical Implications.

This comprehensive review of Spirulina encompasses biotechnology, phycocyanin production, and purification. Bioactive compounds and vital nutrients are investigated during the study. The literature examines the potential therapeutic advantages and clinical applications of Spirulina. This analysis assesses Spirulina consumption and its associated health risks. The current review offers a comprehensive synthesis of the therapeutic applications as well as technologies utilized for the extraction and purification of phycocyanin. Moreover, this discourse delves into the examination of various advantageous techniques for extracting and purifying phycocyanin, encompassing physical, chemical, and enzymatic methods. The data derived from a multitude of studies strongly indicate the potential therapeutic applications of phycocyanin, encompassing its notable attributes as an antioxidant, anti-inflammatory agent, anticancer agent, antiviral agent, antimicrobial agent, antiallergic agent, anti-obesity agent, antihypertensive agent, and an immunological agent.

A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent.

The aim of the present investigation is to identify effective anti-HIV drugs through the in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual screening started with target identification through computation docking and interactions, binding affinity through molecular dynamics, and the ADMET profile through the use of various enzymes. The target study suggests that the target is involved in various stages of HIV replication and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence it. The interaction pattern and simulation study conclude the specific affinity of coumarin pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The initial results led to the determination of 83 virtual amide-like molecules, which were screened through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase enzyme, such as PDB ID "3HVT". The virtual screening study revealed the high affinity of compounds 7d and 7e with the lowest IC50 values of 0.729 and 0.658 µM; moreover, their metabolism pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate. The two compounds were also synthesized and characterized for future in vitro and in vivo studies. The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides the best two molecules and their synthetic route for the development of a more effective drug to combat HIV/AIDS epidemics.

N-Methyl-D-Aspartate (NMDA) Receptor Antagonists and their Pharmacological Implication: A Medicinal Chemistry-oriented Perspective Outline.

N-methyl-D-aspartate (NMDA) receptors, i.e., inotropic glutamate receptors, are important in synaptic plasticity, brain growth, memory, and learning. The activation of NMDA is done by neurotransmitter glutamate and co-agonist (glycine or D-serine) binding. However, the over-activation of NMDA elevates the intracellular calcium influx, which causes various neurological diseases and disorders. Therefore, to prevent excitotoxicity and neuronal death, inhibition of NMDA must be done using its antagonist. This review delineates the structure of subunits of NMDA and the conformational changes induced after the binding of agonists (glycine and D-serine) and antagonists (ifenprodil, etc.). Additionally, reported NMDA antagonists from different sources, such as synthetic, semisynthetic, and natural resources, are explained by their mechanism of action and pharmacological role. The comprehensive report also addresses the chemical spacing of NMDA inhibitors and in-vivo and in-vitro models to test NMDA antagonists. Since the Blood-Brain Barrier (BBB) is the primary membrane that prevents the penetration of a wide variety of drug molecules, we also elaborate on the medicinal chemistry approach to improve the effectiveness of their antagonists.

Bioactive Exploration in Functional Foods: Unlocking Nature's Treasures.

BACKGROUND: Functional foods offer an appealing way to improve health and prevent chronic diseases, and this subject has received much attention lately. They are effective in preventing chronic diseases like cancer, diabetes, heart disease, and obesity, according to research. OBJECTIVE: This work presents an in-depth analysis of functional foods, covering key challenges from a scientific, legal, and commercial perspective. METHODS: Multiple databases were searched to find studies on functional foods included in the systematic literature review. Various aspects of functional foods, from their classification, impact on human wellness, effectiveness in inhibiting chronic diseases, the regulatory environment, global market trends, and industry challenges, are all clarified in this thorough review. RESULTS: This study aims to enhance understanding and establish a pathway for functional foods to be acknowledged as valid choices in the field of dietary supplements. It provides a thorough investigation of bioactive compounds present in functional foods, including but not limited to polyphenols, carotenoids, omega fatty acids, prebiotics, probiotics, and dietary fiber, along with an overview of their potential to mitigate chronic illnesses. We engage in an in-depth exploration of regulatory frameworks, shed light on groundbreaking research advancements, and meticulously examine strategies for commercialization and the variety of global challenges that accompany them. Establishing scientific consensus, navigating complex regulatory processes, dealing with skeptical consumers, and rising levels of competition are all problems that need to be solved in this field. CONCLUSION: The field of functional foods can advance further, promoting better public health outcomes, by deeply comprehending and addressing these complex dimensions.

Quinoline: Synthesis to Application.

This review aims to provide a comprehensive report on the quinoline ring with respect to its synthesis, reactivity, and therapeutic values. The reactivity of quinoline for the metal, electrophile, and other reactive counterparts defines the shape of the quinoline pharmacophore, which is an important part of this report; moreover, its spectroscopic characteristics have been included herein with suitable illustration. The quinoline and its derivatives have been presented as well as the general synthetic approaches along with the new developments in the catalytic system; the relevant information is also summarized under the various separate activity classes. The synthesis of heterocyclic scaffolds has been a concern for scientists, so herein we have tried to include the synthetic parameters of quinoline with regard to the important pharmacological aspects.

Quinoline-3-Carboxylic Acids "DNA Minor Groove-Binding Agent".

BACKGROUND: The lead compounds from the series of 2, 4-disubstituted quinoline-3-carboxylic acid derivatives were selected for the in-silico mechanistic study. The compounds were found selective and potent for the cancer cell. Moreover, the relevant ADME in-silico data also support the safety of lead. OBJECTIVE: The objective of the study is to correlate the interaction of DNA and quinoline derivative, which was reported with the fluorescence microscopy images of cells in-vitro data in the recently published data. METHODS: The detailed interaction study with the DNA dodecanucleotide sequenced d(CGCGAATTCGCG) shows the present lead bounds with the A/T minor groove region of a B-DNA duplex through the important major and minor hydrogen bonds. RESULTS: The present in-silico study supports the interactions of the drug with DNA with sufficient binding interactions and energy. The present study also gives vital information related to the mechanism of drug action, which was initially declared as a DNA targeting molecule through a fluorescence-based target study. CONCLUSION: The substitution at 2nd position (the carbonyl group) of the lead revealed as a hydrogen bond donor/acceptor for adenine and guanine nucleic acid-base pair. The in-silico prediction also confirmed the interaction pattern of the lead with the DNA, which will be further utilized for drug development.

Polymer Grafting and its chemical reactions.

Polymer grafting is a technique to improve the morphology, chemical, and physical properties of the polymer. This technique has the potential to improve the existing conduction and properties of polymers other than charge transport; as a result, it enhances the solubility, nano-dimensional morphology, biocompatibility, bio-communication, and other property of parent polymer. A polymer's physicochemical properties can be modified even further by creating a copolymer with another polymer or by grafting. Here in the various chemical approaches for polymer grafting, like free radical, click reaction, amide formation, and alkylation have been discussed with their importance, moreover the process and its importance are covered comprehensively with their scientific explanation. The present review also covers the effectiveness of the graft-to approaches and its application in various fields, which will give reader a glimpse about polymer grafting and its uses.

Quinoline-3-Carboxylic Acids: A Step Toward Highly Selective Antiproliferative Agent.

BACKGROUND: The 2-styrylquinoline-3-carboxylate derivatives have been reported as antiproliferative agents. OBJECTIVE: The aim of the study was to enhance the selectivity of the drug to the cancer cells. The change in pKa value can be the boost point to enhance the selectivity. The selectivity of the drug will enhance concentration in the cancer cells and will reduce the absorption in the non-cancerous cells. METHODS: The designed hydrolysis of the ester group was obtained through the reported method to change the physiological properties, which was correlated with the in silico and in vitro selectivity studies. The compounds were characterized through important analytical techniques, moreover, the biological results of all compounds were obtained through in vitro cancer (MCF-7 and K562) and non-cancerous (HFK293) cell line. RESULTS: The synthesized compounds exhibited micromolar inhibition with a higher selectivity than their ester parent compounds, however, the compound showed better activity to the cancer cell, because of the minimal distribution of the drug in the non-cancerous cells. The compound 2f and 2l were found more selective and potent. CONCLUSION: The designed 2, 4-disubstituted quinoline-3-carboxylic acid derivatives were evaluated in in vitro cancer (MCF-7 and K562) and non-cancerous (HEK293) cell lines. The most concern issue was resolved by changing the pKa value of compounds, which was calculated by the software base study. The selectivity was correlated with the previously reported ester molecules. The synthesized compounds were characterized by important analytical techniques. The unionized/nonpolar form in the acidic cancer tissue environment, which enhances the drug absorption ion in an acidic medium, was also proved through the in vitro results; hence the compound showed better activity to the cancer cells because of the minimal distribution of the drug in the noncancerous cells. The more selective or less toxic anti-cancer compounds 2f and 2l were reported with all relevant experimental results as in silico Quantitative Estimation of Drug-Likeness (QED) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET).

Quinoline-3-carboxylate Derivatives: A New Hope as an Antiproliferative Agent.

BACKGROUND: The quinoline scaffold has been an attraction due to its pharmacological activities such as anti-HIV, anti-neoplastic, anti-asthmatic, anti-tuberculotic, anti-fungal, and anti-bacterial. OBJECTIVE: The designed quinoline-3-carboxylate derivatives were synthesized through a two-step reaction and evaluated for antiproliferative activity against MCF-7 and K562 cell lines. METHODS: Synthesized compounds were characterized by modern analytical techniques like NMR, 2DNMR, mass, and IR. Moreover, the purity of compounds was analyzed through the HPLC. In the progress of biological results, all synthesized compounds were evaluated for antiproliferative activity against MCF-7 and K562 cell lines. RESULTS: The synthesized compounds exhibited micromolar inhibition in all over the ranges, however, some of the compounds showed better activity than the standard anticancer drug such, as 4m and 4n with the IC50 value of 0.33µM against the MCF-7 cell line, and the compounds 4k and 4m showed potential activity against the K562 cell line with the IC50 value of 0.28µM. The anti-cancer activities of compounds were found to be through the up-regulation of intrinsic apoptosis pathways. CONCLUSION: The biological data of all compounds in both cell lines were utilized for the structural activity relationship of the quinoline-3-carboxylate pharmacophore. The active lead was further validated through rigorous in silico studies for the drug-likeness (QED) and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Here in the present research is utilized for the demonstration of an important pharmacophore, which could be utilized for further development to become a lead as an anticancer agent with minimal toxicity.

Cyclic enaminone as new chemotype for selective cyclooxygenase-2 inhibitory, anti-inflammatory, and analgesic activities.

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.

Microwave Assisted Synthesis of Biorelevant Benzazoles.

The benzazole scaffolds are present in various therapeutic agents and have been recognized as the essential pharmacophore for diverse biological activities. These have generated interest and necessity to develop efficient synthetic methods of these privileged classes of compounds to generate new therapeutic leads for various diseases. The biological activities of the benzazoles and efforts towards their synthesis have been summarized in a few review articles. In view of these, the aim of this review is to provide an account of the developments that have taken place in the synthesis of biorelevant benzazoles under microwave irradiation as the application of microwave heating has long been recognized as a green chemistry tool for speedy generation of synthetic targets. Attention has been focused to those literature reports wherein the use of microwave irradiation is the key step in the formation of the heterocyclic ring system or in functionalization of the benzazole ring system to generate the essential pharmacophoric feature. The convenient and economic way to synthesize these privileged class of heterocycles through the use of microwave irradiation that would be beneficial for the drug discovery scientist to synthesize biologically active benzazoles and provide access to wide range of reactions for the synthesis of benzazoles constitute the theme of this review. Examples have been drawn wherein the use of microwave heating offers distinct advantage in terms of improved product yields and reduction of reaction time as compared to those observed for the synthesis under conventional heating.

Palladium catalyzed Csp2-H activation for direct aryl hydroxylation: the unprecedented role of 1,4-dioxane as a source of hydroxyl radicals.

A novel strategy for direct aryl hydroxylation via Pd-catalysed Csp(2)-H activation through an unprecedented hydroxyl radical transfer from 1,4-dioxane, used as a solvent, is reported with bio relevant and sterically hindered heterocycles and various acyclic functionalities as versatile directing groups.

Cooperative catalysis by palladium-nickel binary nanocluster for Suzuki-Miyaura reaction of ortho-heterocycle-tethered sterically hindered aryl bromides.

The palladium-nickel binary nanocluster is reported as a new catalyst system for Suzuki-Miyaura cross-coupling of ortho-heterocycle-tethered sterically hindered aryl bromides. The inferior results obtained with the reported Pd/Ni salts/complexes or individual Pd/Ni nanoparticles as catalyst reveal the cooperative catalytic effect of the Pd and Ni nanoparticles in the Pd-Ni nanocluster. The broad substrate scope with respect to variation of the 2-arylbenzoxazole moiety and boronic acids, which offers a means for diversity generation and catalyst recyclability, marks a distinct advantage.

2-(2-Arylphenyl)benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation.

The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a-m have been synthesized by Suzuki reaction of 2-(2-bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs.