Deciphering the genetic basis of agronomic, yield, and nutritional traits in rice (Oryza sativa L.) using a saturated GBS-based SNP linkage map.

Developing high-yielding rice varieties that possess favorable agronomic characteristics and enhanced grain Zn content is crucial in ensuring food security and addressing nutritional needs. This research employed ICIM, IM, and multi-parent population QTL mapping methods to identify important genetic regions associated with traits such as DF, PH, NT, NP, PL, YLD, TGW, GL, GW, Zn, and Fe. Two populations of recombinant inbred lines consisting of 373 lines were phenotyped for agronomic, yield and grain micronutrient traits for three seasons at IRRI, and genotyped by sequencing. Most of the traits demonstrated moderate to high broad-sense heritability. There was a positive relationship between Zn and Fe contents. The principal components and correlation results revealed a significant negative association between YLD and Zn/Fe. ICIM identified 81 QTLs, while IM detected 36 QTLs across populations. The multi-parent population analysis detected 27 QTLs with six of them consistently detected across seasons. We shortlisted eight candidate genes associated with yield QTLs, 19 genes with QTLs for agronomic traits, and 26 genes with Zn and Fe QTLs. Notable candidate genes included CL4 and d35 for YLD, dh1 for DF, OsIRX10, HDT702, sd1 for PH, OsD27 for NP, whereas WFP and OsIPI1 were associated with PL, OsRSR1 and OsMTP1 were associated to TGW. The OsNAS1, OsRZFP34, OsHMP5, OsMTP7, OsC3H33, and OsHMA1 were associated with Fe and Zn QTLs. We identified promising RILs with acceptable yield potential and high grain Zn content from each population. The major effect QTLs, genes and high Zn RILs identified in our study are useful for efficient Zn biofortification of rice.

THE QUEST FOR STABLE BOROZENE CORE IN MAIN-GROUP CAPPED INVERSE SANDWICH COMPLEXES, [(HE)2B6H6]2- (E=B, Al, Ga, In, and Tl).

The ubiquitous chemistry of benzene led us to explore ways to stabilise analogous borozene, by capping them with appropriate groups. The mismatch in overlap of ring-cap fragment molecular orbitals in [(HB)2B6H6]2- is overcome by replacing the two BH caps with  higher congeners of boron. We calculated the relative energies of all the polyhedral structural candidates for [(HE)2B6H6]2- (E = Al-Tl) and found hexagonal bipyramid (HBP) to be more stable with Al-H caps. A global minimum search also gives HBP as the most stable structure for [Al2B6H8]2-. The capped B6H6 ring in [(HAl)2B6H6]2- has aromaticity comparable to that of benzene.

Design, synthesis, and anticancer assessment of structural analogues of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an imidazo[1,2-a]quinoxaline-based non-covalent EGFR inhibitor.

In our quest to find improved anticancer therapeutics, we expedite the lead optimization of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an EGFR inhibitor previously discovered in our laboratory through an in-house screening program. The lead optimization was rationally initiated considering the catalytic site of EGFR. We synthesized twenty-nine new analogues of 6b and assessed their anticancer activities. SAR studies highlighted the role of important groups in controlling anticancer activities. Among all, 5a and 5l were found to exhibit improved EGFR inhibition with anticancer asset potential. In silico studies corroborated with in vitro EGFR inhibitory results. The deeper analysis of 5a and 5l revealed that these synthetics could alter the MMP (ΔΨ m) and significantly reduce the ROS levels in lung cancer cells. This is a vital prerequisite for better plausible EGFR inhibitors devoid of cardiotoxicity. qPCR analysis further revealed that the investigational compounds 5a and 5l were able to downregulate the expression of key oncogenes, viz., KRAS, MAP2K, and EGFR. The downregulation of these genes suggests that the investigational compounds could interact and inhibit key players in the signalling cascade along with the EGFR, which may lead to the inhibition of the growth and prognosis of cancer cells via a holistic approach.

The potential of genome editing to create novel alleles of resistance genes in rice.

Rice, a staple food for a significant portion of the global population, faces persistent threats from various pathogens and pests, necessitating the development of resilient crop varieties. Deployment of resistance genes in rice is the best practice to manage diseases and reduce environmental damage by reducing the application of agro-chemicals. Genome editing technologies, such as CRISPR-Cas, have revolutionized the field of molecular biology, offering precise and efficient tools for targeted modifications within the rice genome. This study delves into the application of these tools to engineer novel alleles of resistance genes in rice, aiming to enhance the plant's innate ability to combat evolving threats. By harnessing the power of genome editing, researchers can introduce tailored genetic modifications that bolster the plant's defense mechanisms without compromising its essential characteristics. In this study, we synthesize recent advancements in genome editing methodologies applicable to rice and discuss the ethical considerations and regulatory frameworks surrounding the creation of genetically modified crops. Additionally, it explores potential challenges and future prospects for deploying edited rice varieties in agricultural landscapes. In summary, this study highlights the promise of genome editing in reshaping the genetic landscape of rice to confront emerging challenges, contributing to global food security and sustainable agriculture practices.

Exploring anticancer properties of the phytoconstituents and comparative analysis of their chemical space parameters with USFDA-approved synthetic anticancer agents.

The present review article thoroughly analyses natural products and their derived phytoconstituents as a rich source of plausible anticancer drugs. The study thoroughly explores the chemical components derived from various natural sources, thus emphasizing their unique structural characteristics and therapeutic potential as an anticancer agent. The review contains the critical chemical constituents' in-depth molecular mechanisms, their source's chemical structures and the categories. The review also comprises an exhaustive and comprehensive analysis of different chemical spacing parameters of the anticancer agents derived from natural products. It compares them with USFDA-approved synthetic anticancer drugs up to 2020, thus providing a meaningful understanding of the relationship between natural and synthetic compounds portraying the anticancer assets. The review also delves more deeply into the chemical analysis of the heterocyclic moieties from the natural product arena, illustrating the anticancer mechanisms. The present article is, therefore, expected to serve as a valuable resource for natural product and medicinal chemists, encouraging and promoting an integrated approach to exploit the potential of natural products in drug discovery development and translational research, which have a prerequisite of bench to bedside approach. The work could guide researchers toward innovative approaches for the ever-evolving field of anticancer drug discovery.

Synthesis of ciprofloxacin-linked 1,2,3-triazole conjugates as potent antibacterial agents using click chemistry: exploring their function as DNA gyrase inhibitors via in silico- and in vitro-based studies.

The antibacterial efficacy of some newly developed C-3 carboxylic group-containing ciprofloxacin-linked 1,2,3-triazole conjugates was studied. Twenty-one compounds from three different series of triazoles were synthesized using click chemistry and evaluated for their antibacterial activity against nine different pathogenic strains, including three Gram-positive strains, i.e. Enterococcus faecalis (ATCC29212), Staphylococcus aureus (ATCC25923), Staphylococcus epidermidis (clinical isolate), and six Gram-negative bacterial strains, i.e. Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella typhi (clinical isolate), Proteus mirabilis (clinical isolate), Acinetobacter baumannii (clinical isolate) and Klebsiella pneumonia (clinical isolate). Among the compounds, 10, 10a, 10b, 10c, 10d, 11a, 11f, 12c, 12e and 12f showed excellent activity with MIC values upto 12.5 µg mL-1, whereas the control ciprofloxacin showed MIC values of 0.781-25 µg mL-1 towards various strains. In addition, the low toxicity profile of the synthesized molecules revealed that they are potent antibiotics. Molecular docking and MD analysis were performed using the protein structure of E. coli DNA gyrase B, which was further corroborated with an in vitro assay to evaluate the inhibition of DNA gyrase. The analysis revealed that compound 10b was the most potent inhibitor of DNA gyrase compared to ciprofloxacin, which was employed as the positive control. Furthermore, the structure of two title compounds (11a and 12d) was characterized using single-crystal analysis.

Role of autophagy and proteostasis in neurodegenerative diseases: Exploring the therapeutic interventions.

Neurodegenerative disorders are devastating disorders characterized by gradual loss of neurons and cognition or mobility impairment. The common pathological features of these diseases are associated with the accumulation of misfolded or aggregation of proteins. The pivotal roles of autophagy and proteostasis in maintaining cellular health and preventing the accumulation of misfolded proteins, which are associated with neurodegenerative diseases like Huntington's disease (HD), Alzheimer's disease (AD), and Parkinson's disease (PD). This article presents an in-depth examination of the interplay between autophagy and proteostasis, highlighting how these processes cooperatively contribute to cellular homeostasis and prevent pathogenic protein aggregate accumulation. Furthermore, the review emphasises the potential therapeutic implications of targeting autophagy and proteostasis to mitigate neurodegenerative diseases. While advancements in research hold promise for developing novel treatments, the article also addresses the challenges and complexities associated with modulating these intricate cellular pathways. Ultimately, advancing understanding of the underlying mechanism of autophagy and proteostasis in neurodegenerative disorders provides valuable insights into potential therapeutic avenues and future research directions.

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.

Generation of Broad Protection against Influenza with Di-Tyrosine-Cross-Linked M2e Nanoclusters.

Tyrosine cross-linking has recently been used to produce nanoclusters (NCs) from peptides to enhance their immunogenicity. In this study, NCs were generated using the ectodomain of the ion channel Matrix 2 (M2e) protein, a conserved influenza surface antigen. The NCs were administered via intranasal (IN) or intramuscular (IM) routes in a mouse model in a prime-boost regimen in the presence of the adjuvant CpG. After boost, a significant increase in anti-M2e IgG and its subtypes was observed in the serum and lungs of mice vaccinated through the IM and IN routes; however, significant enhancement in anti-M2e IgA in lungs was observed only in the IN group. Analysis of cytokine concentrations in stimulated splenocyte cultures indicated a Th1/Th17-biased response. Mice were challenged with a lethal dose of A/California/07/2009 (H1N1pdm), A/Puerto Rico/08/1934 (H1N1), or A/Hong Kong/08/1968 (H3N2) strains. Mice that received M2e NCs + CpG were significantly protected against these strains and showed decreased lung viral titers compared with the naive mice and M2e NC-alone groups. The IN-vaccinated group showed superior protection against the H3N2 strain as compared to the IM group. This research extends our earlier efforts involving the tyrosine-based cross-linking method and highlights the potential of this technology in enhancing the immunogenicity of short peptide immunogens.

Pyrano[2,3-c]pyrazole fused spirooxindole-linked 1,2,3-triazoles as antioxidant agents: Exploring their utility in the development of antidiabetic drugs via inhibition of α-amylase and DPP4 activity.

Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate α-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential α-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and α-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics.

Nitrene-transfer from azides to isocyanides: Unveiling its versatility as a promising building block for the synthesis of bioactive heterocycles.

Cross-coupling azide and isocyanide have recently gained recognition as ideal methods for efficiently synthesizing asymmetric carbodiimides. This reaction exhibits high reaction rates, efficiency, and favorable atom/step/redox economy. It enables the nitrene-transfer process, facilitating the formation of C-N bonds and providing a direct and cost-effective synthetic strategy for generating diverse carbodiimides. These carbodiimides are highly reactive compounds that can undergo in-situ transformations into various functional groups and organic compounds, including heterocycles. Developing one-pot and tandem processes in this field has significantly contributed to advancements in organic chemistry. Moreover, the demonstrated utility of these architectural motifs extends to areas such as chemical biology and medicinal chemistry, further highlighting their potential in various scientific applications.

Epigenetic control of cell signalling in cancer stem cells.

The self-renewing cancer stem cells (CSCs) represent one of the distinct cell populations occurring in a tumour that can differentiate into multiple lineages. This group of sparsely abundant cells play a vital role in tumour survival and resistance to different treatments during cancer. The lack of exclusive markers associated with CSCs makes diagnosis and prognosis in cancer patients extremely difficult. This calls for the identification of unique regulators and markers for CSCs. Various signalling pathways like the Wnt/ß-catenin pathway, Hedgehog pathway, Notch pathway, and TGFß/BMP play a major role in the regulation and maintenance of CSCs. Epigenetic regulatory mechanisms add another layer of complexity to control these signalling pathways. In this chapter, we discuss about the role of epigenetic mechanisms in regulating the cellular signalling pathways in CSCs. The epigenetic regulatory mechanisms such as DNA methylation, histone modification and microRNAs can modulate the diverse effectors of signalling pathways and consequently the growth, differentiation and tumorigenicity of CSCs. In the end, we briefly discuss the therapeutic potential of targeting these epigenetic regulators and their target genes in CSCs.

Comparison of subcritical growth parameters of a Y-TZP obtained via cyclic or dynamic fatigue tests.

OBJECTIVE: The objective of this study was to 1) compare the stress corrosion coefficient (n) of a Y-TZP obtained by two fatigue tests: cyclic and dynamic and 2) evaluate the effect of frequency in the characteristic lifetime and the existence of interaction between the cyclic fatigue and slow crack growth. METHODS: A total of 145 Y-TZP specimens were produced in accordance with the manufacturer's instructions. These specimens, measuring 4.0 × 3.0 × 25.0 mm, were used for dynamic (n = 70) and cyclic fatigue tests (n = 75). The specimens were obtained from CAD/CAM blocks, sectioned, and sintered in a furnace at 1530 °C with a heating rate of 25 °C/min. They were tested in their "as-sintered" form without any additional surface treatment. The fatigue tests were conducted using a four-point bending to obtain the slow crack growth parameters (n). The cyclic fatigue test was also conducted in two frequencies (2 and 10 Hz), using stress levels between 350 and 600 MPa. Data from these tests were analyzed using ASTM C 1368-00 formulas and Weibull statistics. Scanning electron microscope (SEM) was used for fracture surface analysis to identify the origin of the fracture. Critical defect size was measured and used, along with flexural strength values, to estimate fracture toughness. Dynamic fatigue test data were used to obtain subcritical crack growth (SCG) parameters and perform Weibull statistical analysis. The cyclic fatigue data were used in the General Log-linear Model equation using the ALTA PRO software. Data were analyzed using one-way ANOVA followed by Tukey post-hoc tests and Student's t-test at a significance level of p ≤ 0.05. RESULTS: In the dynamic fatigue test, the values obtained for σfo and n were 667 and 54, respectively. This parameter indicates how the strength of the material diminishes over time due to internal cracks. The Weibull parameters obtained from the same test results were m = 7.9, σ0 = 968, 9 and σ5% = 767, which indicates the reliability of the material. The Weibull parameters obtained by cyclic fatigue were statistically similar for the two frequencies used, the m* was 0.17 (2 Hz) and 0.21 (10 Hz); characteristic lifetimes (η) were 1.93 × 106 and 40,768, respectively. The n values obtained by cyclic fatigue were 48 and 40 at frequencies of 2 and 10 Hz, respectively. There was no effect of the frequency, the stress level or the interaction of the two in the Y-TZP lifetime, when analysed by General Log Linear Model. SIGNIFICANCE: the n values obtained by cyclic and dynamic fatigue tests showed no statistically significant difference and the effect of frequency in the characteristic lifetime and the existence of interaction between the cyclic fatigue and subcritical growth were not observed in the tested specimens.

Efficient gene editing in induced pluripotent stem cells enabled by an inducible adenine base editor with tunable expression.

The preferred method for disease modeling using induced pluripotent stem cells (iPSCs) is to generate isogenic cell lines by correcting or introducing pathogenic mutations. Base editing enables the precise installation of point mutations at specific genomic locations without the need for deleterious double-strand breaks used in the CRISPR-Cas9 gene editing methods. We created a bulk population of iPSCs that homogeneously express ABE8e adenine base editor enzyme under a doxycycline-inducible expression system at the AAVS1 safe harbor locus. These cells enabled fast, efficient and inducible gene editing at targeted genomic regions, eliminating the need for single-cell cloning and screening to identify those with homozygous mutations. We could achieve multiplex genomic editing by creating homozygous mutations in very high efficiencies at four independent genomic loci simultaneously in AAVS1-iABE8e iPSCs, which is highly challenging with previously described methods. The inducible ABE8e expression system allows editing of the genes of interest within a specific time window, enabling temporal control of gene editing to study the cell or lineage-specific functions of genes and their molecular pathways. In summary, the inducible ABE8e system provides a fast, efficient and versatile gene-editing tool for disease modeling and functional genomic studies.

Imidazoles as Serotonin Receptor Modulators for Treatment of Depression: Structural Insights and Structure-Activity Relationship Studies.

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.

Generation and characterization of induced pluripotent stem cell line IITGi001-A derived from adult human primary dermal fibroblasts.

Adult human primary dermal fibroblasts [ATCC (PCS-201-012)] were reprogrammed by transfection of oriP/EBNA-1 based episomal plasmids expressing OCT3/4, SOX2, KLF4, L-MYC, LIN28 and a p53 shRNA (Okita et al., 2011) to give rise to induced pluripotent stem cells (iPSCs). These iPSCs expressed core pluripotency markers, maintained normal karyotype, and showed tri-lineage differentiation potential. Further, the absence of episomal plasmid integration in this iPSC line was confirmed by genomic PCR. In addition, DNA fingerprinting of fibroblast and iPSC DNA by microsatellite analysis confirmed the genetic identity of this cell line. This iPSC line was shown to be free from mycoplasma contamination.

Delivery of gold nanoparticle-conjugated M2e influenza vaccine in mice using coated microneedles.

As a prospective influenza vaccination platform, a microneedle patch offers advantages such as self-administration and reduction of needle-phobia-associated vaccination avoidance. In an effort to design a broadly protective influenza vaccine we have previously developed a vaccine formulation containing the highly conserved ectodomain sequence of the M2 influenza protein (M2e) attached to the surface of gold nanoparticles (AuNPs) with CpG as a soluble adjuvant (AuNP-M2e + sCpG). Our previous studies have used the intranasal route for vaccination and demonstrated broad protection from this vaccine. Here we asked the question whether the same formulation can be effective when administered to mice using microneedles. We demonstrate that the microneedles can be coated with AuNP-M2e + sCpG formulation, and the AuNPs from the coating can be readily resuspended without aggregation. The AuNPs were delivered with high efficiency into murine skin, and the AuNPs cleared the skin within 12 h of microneedle treatment. After vaccination, strong M2e-specific humoral and cellular responses were stimulated, and the vaccinated mice were 100% protected following a lethal challenge with influenza A/PR/8/34 (H1N1).

Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX.

Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. SIGNIFICANCE: Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.

Electro-organic synthesis of C-5 sulfenylated amino uracils: Optimization and exploring topoisomerase-I based anti-cancer profile.

Cancer is spreading worldwide and is one of the leading causes of death. The use of existing chemotherapeutic agents is frequently limited due to side effects. As a result, it is critical to investigate new agents for cancer treatment. In this context, we developed an electrochemical method for the synthesis of a series of thiol-linked pyrimidine derivatives (3a-3p) and explored their anti-cancer potential. The biological profile of the synthesized compounds was evaluated against breast (MDAMB-231 and MCF-7) and colorectal (HCT-116) cancer cell lines. 3b and 3d emerged to be the most potent agents, with IC50 values ranging between 0.98 to 2.45 µM. Target delineation studies followed by secondary anticancer parameters were evaluated for most potent compounds, 3b and 3d. The analysis revealed compounds possess DNA intercalation potential and selective inhibition towards human topoisomerase (hTopo1). The analysis was further corroborated by DNA binding studies and in silico-based molecular modeling studies that validated the intercalating binding mode between the compounds and the DNA.

Design and Development of COX-II Inhibitors: Current Scenario and Future Perspective.

Innate inflammation beyond a threshold is a significant problem involved in cardiovascular diseases, cancer, and many other chronic conditions. Cyclooxygenase (COX) enzymes are key inflammatory markers as they catalyze prostaglandins production and are crucial for inflammation processes. While COX-I is constitutively expressed and is generally involved in "housekeeping" roles, the expression of the COX-II isoform is induced by the stimulation of different inflammatory cytokines and also promotes the further generation of pro-inflammatory cytokines and chemokines, which affect the prognosis of various diseases. Hence, COX-II is considered an important therapeutic target for drug development against inflammation-related illnesses. Several selective COX-II inhibitors with safe gastric safety profiles features that do not cause gastrointestinal complications associated with classic anti-inflammatory drugs have been developed. Nevertheless, there is mounting evidence of cardiovascular side effects from COX-II inhibitors that resulted in the withdrawal of market-approved anti-COX-II drugs. This necessitates the development of COX-II inhibitors that not only exhibit inhibit potency but also are free of side effects. Probing the scaffold diversity of known inhibitors is vital to achieving this goal. A systematic review and discussion on the scaffold diversity of COX inhibitors are still limited. To address this gap, herein we present an overview of chemical structures and inhibitory activity of different scaffolds of known COX-II inhibitors. The insights from this article could be helpful in seeding the development of next-generation COX-II inhibitors.