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Donepezil hydrochloride (DPL) and Embelin (EMB) loaded Nanostructured Lipid Carriers (NLCs) have been developed and optimized to achieve optimal drug loading, safer nasal delivery, effective neuronal/cell uptake, enhanced brain accessibility, controlled release, and desired therapeutic effect. Molecular docking studies demonstrated that both drugs bind effectively to AchE with interaction energies of -48.5319 and − 65.7525, respectively, indicating a synergistic approach. The hydrophobic interactions with target proteins facilitate the transportation of drugs through brain hydrophobic channels to provide a desired pharmacological response. N2a cell line investigation advised a 1:1 ratio of DPL and EMB to have the greatest possible synergistic effect based on the MTT assay. NLCs were fabricated by hot emulsification probe sonication method and optimized using QbD-based Central Composite Rotatable Design (CCRD). Optimized NLCs with a diameter of 180.2 nm were suitable for axonal uptake. A low Polydispersity index (PDI) score of 0.37 and Zeta Potential (ZP) of -12 mV indicated a uniform monodisperse system with persistent and stable dispersion properties. The NLCs demonstrated sustained drug release, DPL released at 90.72 ± 1.00%, and EMB at 81.30 ± 0.52% in 24 h. The Korsemeyer-Peppas model proved to be the most accurate fit due to its strong correlation. Ex vivo permeation and CLSM studies revealed superior goat nasal mucosa penetration of NLCs over suspension with a higher fluorescence level, up to 35 μm. NLCs treated nasal mucosa exhibited no erosion or interstitial gaps in the histopathological study. Moreover, NLCs were nontoxic and non-irritating, with a HET CAM score of 0.68 ± 0.05, indicating safe nasal delivery. The cellular uptake study showed a preponderance of the NLCs in the Cell's cytoplasm, indicating ready uptake by N2a cells. Hence, intranasal therapy with the DPL and EMB-loaded NLCs could be a practical and promising implementation. Further in vivo, and clinical studies will be required to establish the formulation's efficacy in treating Alzheimer's disease (AD). Graphical Abstract [ABSTRACT FROM AUTHOR]

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, β-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract Image 1 Highlights • Piperidine is a six membered heterocyclic moiety which comprises of five methylene groups (-CH 2 -) & one amine group (-NH-). • Piperidine has an excellent anticancer profile. • Analysis of structure activity relationships of piperidine derivatives will help in designing newer anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract Image 1 Highlights • Pyrrole is a heterocyclic aromatic five membered multiple pharmacophoric template. • The name pyrrole came from the Greek word 'pyrrols' means fiery from the reaction. • Pyrroles exhibit lower basicity due to delocalization of lone pair of electrons of nitrogen atom in the pyrrole ring. • The NH and CH protons are moderately acidic and can be deprotonated with strong bases, showing its nucleophilic nature. [ABSTRACT FROM AUTHOR]

A new series of 3-[2-(5-mercapto-4-phenyl-4 H -1,2,4-traiazol-3-yl)ethyl] quinoxalin-2(1 H ) - one ( 5a-v ) derivatives was synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti-denaturation assay) and p38α MAPK inhibition. Few selected compounds ( 5a , 5e , 5f , 5g , 5h , 5l , 5q and 5u ) were studied for their in vivo anti-inflammatory activity, ulcerogenicity and lipid peroxidation potential. Compounds 5e and 5f were found to be the most active in the series showing 83.45% and 84.15% anti-inflammatory activity respectively when compared to diclofenac sodium (83.22%). They were also found to have low ulcerogenic potential and lipid peroxidation. The p38α MAP kinase inhibition of the compounds 5e and 5f was also found to be slightly better than the standard SB 203580. The compounds were also docked against p38α MAP kinase enzyme in order to predict their binding mode. Compounds 5e and 5f showed stronger binding with an additional hydrogen bond interaction with ASP-168 which was not observed in SB 203580. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To prepare and evaluate some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6-chlorosubstitutedphenyl pyrimidines as antimicrobial agents. Methods: Some 2-piperidinomethylamino-4-(7-H/substitutedcoumarin-3-yl)-6-chlorosubstitutedphenyl pyrimidines were prepared by reacting 2-amino-4-(7-H/substitutedcoumarin-3-yl)-6-(chlorosubstitutedphenyl) pyrimidines with piperidine and formaldehyde. The chemical structures of the synthesized compounds were elucidated by Fourier transform infrared (FTIR), 1H-nuclear magnetic resonance (1H-NMR), mass spectrometry and elemental analysis. These compounds were investigated for their antimicrobial activity against ten bacteria and five fungi by serial plate dilution method using standard drugs, namely, ofloxacin and ketoconazole, respectively, and their minimum inhibitory concentrations (MICs) were also determined. Results: A total of eighteen new compounds (1a-18a) were synthesized. Compound 6a (MIC = 50 μg/mL; p < 0.05 or less) displayed the highest activity against S. aureus, E. faecalis, S. epidermidis, B. subtilis, and B. cereus. Compound 6a further showed good activity (MIC = 25 μg/mL; p < 0.05 or less) against E. coli; P. aeruginosa K. pneumonia, B. bronchiseptica, and P. vulgaris. Compounds 6a (MIC = 25 μg/mL; p < 0.0001) and 17a (MIC = 25 μg/mL; p < 0.0001) displayed very good activity against C. albicans, A. niger, A. flavus, M. purpureous, and P. citrinum, respectively. Analysis of structure-activity relationship revealed that the presence of bromo group at 7-postion of the coumarin moiety along with the 4-chlorophenyl group at position-6 of the pyrimidine ring is critical for antimicrobial activity against Gram-positive bacteria, Gram negative bacteria and fungi. Conclusion: The synthesized 2-piperidino derivatives are better antifungal and antibacterial agents than the earlier reported 2-morpholino derivatives, but require further investigations against other microbial strains to ascertain their broad spectrum antimicrobial activity. [ABSTRACT FROM AUTHOR]

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 followup may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy. [ABSTRACT FROM AUTHOR]

Abstract: A number of 5-(4-substituted phenyl)-2-(substituted benzylsulfanyl)-4-(substituted phenyl)-6-methyl-1,4-dihydro-5-pyrimidine carboxamides (1–30) were designed and synthesized keeping in view the structural requirements as suggested in the pharmacophore model for antihypertensive activity. All the synthesized compounds were tested for antihypertensive activity by non-invasive blood pressure (NIBP) measurements (tail-cuff method) in rats. Almost all the tested compounds displayed considerable decrease in the blood pressure as compared to control. Thirteen compounds showed significant antihypertensive activity comparable to the standard drug nifedipine. [ABSTRACT FROM AUTHOR]

Abstract: A number of N-(4,6-substituted diphenylpyrimidin-2-yl) semicarbazones (4a–t) were synthesized and tested for their anticonvulsant activity against the two seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). All the synthesized compounds possessed the four essential pharmacophoric elements for good anticonvulsant activity. Most of the compounds displayed good anticonvulsant activity with lesser neurotoxicity. To assess the unwanted effects of the compounds on liver, estimation of enzymes and proteins was carried out. [Copyright &y& Elsevier]

In traditional herbal medicine, the Gymnema species has been well known for various therapeutic activities such as anti-diabetic, anti-inflammatory, anti-bacterial, anti-arthritic, anti-hyperlipidemic, cytotoxic, and immunostimulatory activities. This review is an effort to analyse all the recent studies done to explore the anti-diabetic potential of traditional Gymnema species. Gymnema sylvestre (Retz.) R.Br. ex Sm. is an important member of the Apocynaceae family that has been used to treat a variety of diseases, the most studied of which is diabetes. This action is mostly due to the pharmacologically active phytoconstituents present in its extract, which include gymnemic acids, triterpenoid saponin glycosides, and so on. Numerous other Gymnema species have also demonstrated a similar pharmacological action. The goal of this study is to give a critical overview of the available data on Gymnema species that are used to treat diabetes. The major goal of this study is to give up-to-date knowledge on ethnopharmacology, botany, pharmacology, and structure-activity relationships of Gymnema species from 2016 to 2020, as well as potential future research. The potential of using medicinal plants for alleviating symptoms of diabetes is recently being recognized. This review aims to summarize the available data and highlight both the potential and shortcomings of using Gymnema therapeutically. This knowledge can further be used to develop more therapeutically effective drugs derived from Gymnema. Data for Gymnema species was obtained using a mix of several search terms from online databases such as PubMed, SCOPUS, and Europe PMC. Other literature surveys relevant to traditional knowledge, phytochemistry, pharmacology, or structure-activity relationship activity were also used as reference. Several methods by which Gymnema species extracts exert their effects have been investigated, and a summary of the newly discovered chemicals isolated from the plant in the previous five years has been provided. SAR based evaluation has been carried out for a total of 27 pharmacologically active compounds belonging to three species of Gymnema genus (Gymnema sylvestre, Gymnema latifolium, and Gymnema inodorum). These compounds demonstrated the critical significance of plant medicines for diabetes management. Numerous heterocyclic compounds have anti-diabetic action and may serve as a starting point for the design and identification of new diabetes inhibitors. This study aims to provide researchers with a better understanding of the antidiabetic potential Gymnema species, as well as an outline of prospective future developments. It was concluded after studying the evaluation done in the last 5 years that although extracts of Gymnema have shown good antidiabetic potential, further modifications in the structures could result in the development of more potent and safer compounds. [Display omitted] • Diabetes mellitus affects multiple systems with combination approach being choice of treatment. • Gymnema species show plethora of biological activities by virtue of synergistic effect on multiple targets. • This review enlists various mechanisms by which antidiabetic action is brought about using Gymnema species. • Antidiabetic potential was explored after studying research done in the last 5 years. • Rigorous extraction can result in isolation of novel and more potent compounds. [ABSTRACT FROM AUTHOR]

[Display omitted] • GPR119 agonist based analogues for treating Diabetes mellitus. • Modifying GPCR activity for modern drug development. • Future perspectives and directions were discussed. Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in β-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015–2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2. [ABSTRACT FROM AUTHOR]

• Convulsion is a neurological condition triggered by recurring unprovoked seizure that may upset physical, mental and behavioural operations. • SAR and docking studies of newer anti-epileptic agents have been explained. • Novel anti-epileptic agents have been established with an improved safety, potency and efficacy. 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. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• A UPLC-MS/MS method for determination of tamoxifen and sulphoraphane in rat plasma. • The method was validated as per US FDA guideline for bioanalytical method. • Application to an oral pharmacokinetic study in rats. Tamoxifen (TAM) is the choice of a drug approved by the Food and Drug Administration (FDA) for the treatment of estrogen-positive receptor (ER+) breast cancer. Sulphoraphane (SFN), a natural plant antioxidant compound, also acts on estrogen-positive breast cancer receptor. Thus, a combination of TAM with SFN is preferred as it helps to minimize the drug-related toxicity and increases the therapeutic efficacy by providing synergistic anticancer effects of both drugs. In the present study, a new simple, sensitive, precise, and selective UPLC-MS/MS method was developed for the simultaneous quantification of tamoxifen and sulphoraphane using propranolol as an internal standard (IS) in rat plasma. Chromatographic separation was achieved on reverse phase Acquity UPLC BEH C18 column (50 mm × 2.1 mm, i.d., 1.7 μm) with an isocratic mobile phase composed of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) (80:20, v/v) at a flow-rate of 0.4 mL/min. The detection and quantification of analytes was performed on Waters ZsprayTM Xevo TQD using selected-ion monitoring operated under a positive electrospray ionization mode. The transitions were m / z = 372.0 [M+H]+ → 71.92 for tamoxifen, m / z = 177.9 [M+H]+ → 113.9 for sulphoraphane and m / z = 260.3 [M+H]+ → 116.1 for propranolol. The method was linear over the concentration range of 8–500 ng/mL (r2 = 0.9996) for tamoxifen, 30–2000 ng/mL (r2 = 0.9998) for sulphoraphane with insignificant matrix effect and high extraction recovery on spiked quality control (QC) samples. The intra- and inter-batch precisions and accuracy were within the acceptable limits, and both the analytes were found to be stable throughout the short term, long term and freeze thaw stability studies. The validated method was successfully applied for the simultaneous estimation of TAM and SFN in an oral pharmacokinetic study in female Wistar rats. This developed UPLC-MS/MS method could be a valuable tool for future pharmacokinetic interaction, therapeutic drug monitoring and pharmacokinetic characterization of novel formulations. [ABSTRACT FROM AUTHOR]

AbstractThe objective of the present study was to develop and optimize Khellin-loaded ethosomes formulation to enhance the topical delivery of Khellin for the management of psoriasis. Based on vesicle size, polydispersity (PdI) and encapsulation efficiency, the formulation was optimized using the "3-factor 3-level", Box-Behnken design (BBD). Antioxidant, Anti-inflammatory and Anti-psoriatic activity were further assessed for the optimized formulation. The optimized formulation carried vesicles with a size of 214.64 ± 0.04 nm, PdI 0.387 ± 0.001 and an encapsulation efficiency of 68.38 ± 0.01%. Rhodamine-B loaded formulation was applied to mice skin, and the penetration depth was measured using confocal laser scanning microscopy (CLSM). It was found that the Rhodamine-B solution penetrated mice’s skin to a depth of 20.0 µm. However, the Rhodamine-B loaded ethosomes formulation penetrated mice’s skin to a depth of 55.0 µm. Further, the Khellin-loaded ethosomes formulation possessed strong antioxidant activity, presented a good reduction in paw edema, and showed good anti-inflammatory activity. In addition, the prepared Khellin-loaded ethosomes formulation exhibited considerable effects against psoriasis. [ABSTRACT FROM AUTHOR]

In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 ( 2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20 , 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA 2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. [ABSTRACT FROM AUTHOR]

Neratinib, a tyrosine kinase inhibitor, was very recently approved by USFDA in 2017 as an anticancer drug to treat of HER2 positive breast cancers. The present work provides an account on the development of a validated bioanalytical UPLC–MS/MS method for quantification of neratinib and internal standard (imatinib) in rat plasma and tissue homogenates. A UPLC having a 100 mm C18 column (1.7 μm sized particles) was used with acetonitrile (0.1% formic acid): 2 mMol of ammonium acetate in water (pH 3.5) as the mobile phase. An efficient chromatographic separation was performed and detection was achieved by monitoring precursor-to-product ion transitions with m/z 557.29 → 112.06 for neratinib and m/z 494.43 → 294.17 for IS. The method demonstrated excellent linearity in the spiked plasma drug concentrating ranging between 1 and 800 ng.mL−1 (r2 = 0999), with lower limit of quantification (LLOQ) was observed at 1 ng.mL−1. Intra-assay and inter-assay precision relative standard deviations were found to be within 6.58. Mean extraction recovery for neratinib and IS were 99.44 and 99.33%, while matrix effect for neratinib and IS was ranging between −4.35 and − 3.66%, respectively. Overall, the method showed successful applicability in pharmacokinetic analysis of pure various formulations in Wistar rat plasma. [ABSTRACT FROM AUTHOR]

A series of thiazolidin-4-one (2a-h; 3a-h), azetidin-2-one (4a-h) and 1,3,4-oxadiazole (5a-h) derivatives of isoninicotinic acid hydrazide (INH) were synthesized in order to obtain new compounds with potential anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities. The structures of the new compounds were supported by their IR, ¹H-NMR and mass spectral data. All compounds were evaluated for their anti-inflammatory activity by the carrageenan-induced rat paw edema test method. Eleven of the new compounds, out of 32, showed very good anti-inflammatory activity in the carrageenan-induced rat paw edema test, with significant analgesic activity in the tail immersion method together with negligible ulcerogenic action. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde content (MDA), which is one of the by-products of lipid peroxidation. The study showed that the compounds inhibited the induction of gastric mucosal lesions and it can be suggested from the results that their protective effects may be related to inhibition of lipid peroxidation in the gastric mucosa. [ABSTRACT FROM AUTHOR]

COVID-19 has had an impact on human quality of life and economics. Scientists have been identifying remedies for its prevention and treatment from all possible sources, including plants. Nigella sativa L. (NS) is an important medicinal plant of Islamic value. This review highlights the anti-COVID-19 potential, clinical trials, inventions, and patent literature related to NS and its major chemical constituents, like thymoquinone. The literature was collected from different databases, including Pubmed, Espacenet, and Patentscope. The literature supports the efficacy of NS, NS oil (NSO), and its chemical constituents against COVID-19. The clinical data imply that NS and NSO can prevent and treat COVID-19 patients with a faster recovery rate. Several inventions comprising NS and NSO have been claimed in patent applications to prevent/treat COVID-19. The patent literature cites NS as an immunomodulator, antioxidant, anti-inflammatory, a source of anti-SARS-CoV-2 compounds, and a plant having protective effects on the lungs. The available facts indicate that NS, NSO, and its various compositions have all the attributes to be used as a promising remedy to prevent, manage, and treat COVID-19 among high-risk people as well as for the therapy of COVID-19 patients of all age groups as a monotherapy or a combination therapy. Many compositions of NS in combination with countless medicinal herbs and medicines are still unexplored. Accordingly, the authors foresee a bright scope in developing NS-based anti-COVID-19 composition for clinical use in the future. [ABSTRACT FROM AUTHOR]

This document is an editorial from the journal Frontiers in Chemistry titled "Medicinal chemistry of active pharmaceutical ingredients of drug products." It discusses the importance of active pharmaceutical ingredients (APIs) in drug products and the need for suitable APIs to comply with specific dosage form characteristics. The editorial highlights three research studies related to medicinal chemistry. The first study explores the anti-ulcerative colitis effects of extracts from Calliandra haematocephala. The second study focuses on the quality evaluation of compounds in leaves of six Taxus species. The third study investigates the chemical fingerprinting and biological properties of the essential oil from Eucalyptus globulus leaves. The authors conclude that these studies provide valuable insights into potential therapeutic approaches for various diseases. [Extracted from the article]

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD. [Display omitted] • Quality by Design (QbD) approach was employed in preparation of nanoparticles. • Sirolimus loaded PLGA nanoparticles were successfully functionalized with chitosan. • Chitosan functionalization enhanced cellular uptake and scleral penetration. • SIR-CH-PLGA nanoparticles were safe with higher anti-angiogenic potential. [ABSTRACT FROM AUTHOR]

The over expression of EGFR has been recognized as the driver mechanism in the occurrence and progression of carcinomas such as lung cancer, breast cancer, pancreatic cancer, etcetera. EGFR receptor was thus established as an important target for the management of solid tumors. The occurrence of resistance caused as a result of mutations in EGFR has presented a formidable challenge in the discovery of novel inhibitors of EGFR. This has resulted in the development of three generations of EGFR TKIs. Newer mutations like C797S cause failure of Osimertinib and other EGFR TKIs belonging to the third-generation caused by the development of resistance. In this review, we have summarized the work done in the last five years to overcome the limitations of currently marketed drugs, giving structural activity relationships of quinazoline-based lead compounds synthesized and tested recently. We have also highlighted the shortcomings of the currently used approaches and have provided guidance for circumventing these limitations. Our review would help medicinal chemists streamline and guide their efforts towards developing novel quinazoline-based EGFR inhibitors. Image 1 • Six quinazoline-based EGFR TKIs are in market for treatment of 10–30% of NSCLC cases. • Current limitations like acquired resistance hinder effective use of available drugs. • Last 5 years-synthesis of new quinazoline leads to overcome the existing challenges. • Next decade-focus on designing drugs targeting EGFR harboring tertiary mutations. • Focus would also be on combination approach targeting multiple pathways to treat cancer. [ABSTRACT FROM AUTHOR]

Background: The use of Ammi majus L. for the treatment of various diseases has been reported by many. Its umbelliferous fruits possess khellin that is responsible for various pharmacological activities and used in treating psoriasis and vitiligo. Objectives: The study objective was to analyze the optimization of extraction parameters of khellin from A. majus L. by response surface methodology (RSM). Materials and Methods: Box–Behnken Design (BBD) of RSM was used for optimization needs. Quantification of khellin in extracts was done by high performance thin-layer chromatography using a mix of ethyl acetate: toluene: formic acid, and the peaks were monitored at 254 nm. Results: Among the explored traditional modes and ultrasound-assisted extraction (UAE), UAE was found to be the most ideal for khellin extraction, with methanol being the most suitable solvent. The applied BBD established a quadratic model for the experimental setup with the regression coefficient of 0.998. The optimal conditions were set up as – extraction temperature: 63.84°C, extraction time: 29.51 min. and solvent-to-drug ratio: 21.64 v/w, which yielded 6.21% w/w of khellin. Contrarily, under the modified experimental conditions, 6.86% w/w of khellin was extracted. Conclusion: It was concluded that all the variables studied significantly affected khellin yield. Moreover, a contemporary green extraction mode stood out to be the best for khellin extraction. [ABSTRACT FROM AUTHOR]

• COX is a family of isozymes responsible for the catalysing reactions of Arachidonic acid. • COX-2 inhibitors based on Pyrazole, Indole, Oxazole, Pyridine and Pyrrole are studied using SAR and docking. • Novel COX-2 inhibitors have been developed with an improved safety profile and with a higher potency. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7μm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats. [ABSTRACT FROM AUTHOR]

• Coumarin based histidine derivative with anticryptococcal activity. • Identification of most active compound 11n against Cryptococcus neoformans. • Detailed biological studies of 11n by time kill assay, confocal laser scanning microscopy and scanning electron microscopy. • Molecular docking, MMGBASA and ADMET analysis of the synthesized derivatives. • Molecular dynamics studies of 11n. Despite numerous attempts to develop new pharmacophores as promising antimicrobials, the coumarin scaffold remains one of the foremost sought moiety in the design of molecules. Herein, we report the new structural class of coumarin-based C-2 cycloalkylated histidine hybrids as potential antimicrobial agents. The most promising compound 11n displayed IC 50 of 0.27 µg/mL, 1.1 µg/mL, 4.4 µg/mL and 4.4 µg/mL against Crptococcus neoformans, Candida albicans, Escherichia coli and Staphylococcus aureus , respectively. Interestingly, 11n displays fungicidal activity on growing cryptococcal cells with high selectivity. The presence of 11n lead to the permeabilization of fungal cells as confirmed by propidium iodide uptake study. Moreover, scanning electron microscopy revealed that it causes shrinkage and disruptions in the cell membranes, which is responsible for the cell lysis. Molecular docking analysis revealed that 11n have a distinct H-bonding with TYR409 and TRP94 which are lacking in the co-crystal ligand and are predicted that these are responsible for the potency of the compound. Moreover, the results of the MD simulation analysis showed that the protein-ligand complex exhibits substantial binding interactions with a variety of amino acids and is stable for 100 ns. Additionally, ADMET analysis depicted that these molecules have considerable ADME properties. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Icariin, a major component of Epimedium species and a mild phosphodiesterase 5 (PDE-5) inhibitor, was evaluated for the prevention of myocardial oxidative stress in isoproterenol (ISO)-challenged Wistar rats. Objective: This study aimed to evaluate the cardioprotective action of icariin in ISO-intoxicated rats. Materials and Methods: Rats were daily treated with icariin (1, 5, and 10 mg/kg, p.o.) and sildenafil (0.7 mg/kg, i.p.) for 15 days. Oxidative stress was induced by subcutaneous administration of ISO (85 mg/kg s.c) in two consecutive doses at an interval of 24 h on 14th and 15th day of the study. After induction, rats were anesthetized for recording the electrocardiogram (ECG) and then sacrificed to perform immunohistochemistry and biochemical assays of heart tissue. Results: ISO treatment resulted in a marked increase in lipid peroxidation, serum markers (lactate dehydrogenase [LDH], creatine kinase-MB [CK-MB], and C-reactive protein [CRP]), and infarct size and a significant decrease in the level of reduced glutathione (GSH) and endogenous antioxidant enzymes in the myocardium. Lowering of arterial blood pressure and alteration in ECG showed significant alteration in cardiac hemodynamics. Hematoxylin and eosin staining of the cardiac tissue showed considerable myocardial damage. Pretreatment with icariin (5 and 10 mg/kg, p.o.) and sildenafil (0.7 mg/kg, i.p) significantly decreased the elevated lipid peroxidation, LDH, CK-MB, and CRP. Moreover, the results also showed an increase in endogenous antioxidants and protein expression of nuclear factor-like 2 (Nrf-2) when compared to the ISO-treated group. Conclusion: The results indicated that icariin significantly ameliorates the ISO-induced oxidative stress and restores membrane integrity and cellular damage. Thus, we can conclude that the activation of Nrf-2 signaling and PDE-5 inhibition by icariin is possibly responsible for the cardioprotection. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of 5-aryl-3-[(2-chloroquinolin-3-yl)methylene] furan-2(3H)-ones (3a-p) were synthesized. The required 3-(substituted benzoyl)propionic acids 2a-d were prepared under Friedel-Crafts acylation reaction conditions. The substituted 2-chloroquinoline-3-carboxaldehydes 1a-d were synthesized by reaction of substituted phenylethanone oxime with phosphorus oxychloride in presence of dimethylformamide using the Vilsmeier-Haack reaction method. These compounds were screened for their anti-inflammatory and antibacterial activities along with their ulcerogenic and lipid peroxidation potentials. The compounds that showed significant anti-inflammatory activity were further screened for their analgesic activity. The compounds were less toxic in terms of ulcerogenicity as compared to a standard, which was also supported by lipid peroxidation studies. The antibacterial activities were performed against Staphylococcus aureus and Escherichia coli. Compounds 3f, 3n and 3o showed significant activity against both S. aureus and E. coli having an minimum inhibitory concentration (MIC) value of 6.25 μg mL-1. [ABSTRACT FROM AUTHOR]

In this study, a series of novel 1,2,4-triazolo-[3,4- b]-1,3,4-thiadiazole ( 6a--g) and 1,3,4-oxadiazole ( 7a--g, 8) were synthesized from N-(6-chlorobenzo[ d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class. Antimicrobial properties of the title compound derivatives were investigated against one Gram (++) bacteria ( Staphylococcus aureus), three Gram (−−) bacteria ( Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungi ( Candida albicans, Aspergillus niger, Aspergillus flavus, Monascus purpureus and Penicillium citrinum) using serial plate dilution method. The investigation of antibacterial and antifungal screening data revealed that all the tested compounds showed moderate to good inhibition at 12.5--100 µµg/mL in DMSO. It has been observed that triazolo-thiadiazole derivatives are found to be more active than 1,3,4-oxadiazole derivatives against all pathogenic bacterial and fungal strains. [ABSTRACT FROM AUTHOR]

Cuscuta reflexa Roxb. (C. reflexa) is a well-known traditional herbal plant, with numerous inherent therapeutic potentials including anticancer, antitumor, antibacterial, analgesic, anthelmintic, laxative and others. Moreover, the anticancer and antitumor potentials of this herb are ongoing with several trails, thus an attempt was made to assess the anticancer and hepatoprotective potentials of traditional C. reflexa herbs. The dried ethanolic extract of C. reflexa was tested for acute oral toxicity in the treated animals subsequently their behavioral, neurological, and autonomic profiles changes were observed. T he preliminary anti-cancer effects of extracts against 1, 2- Dimethyl hydrazine (DMH) induced animals were assessed through barium enema X-ray, colonoscopy, and Aberrant crypt foci (ACF) studies. The blood samples of the animals (treated and untreated) were collected and their in-vitro histological parameters were evaluated by the experienced technician. It was observed that C. reflexa significantly reduced Disease activity indexing (DAI) level and ACF counting, as well as demonstrated similar activity as of the standard drug 5-Fluorouracil (5-FU). Histopathological results revealed that the apoptotic bodies decreased in the DMH-induced group (group II) during cancer progression while in 5-FU treated (group III) and C. reflexa treated (group IV and V) animals the apoptotic bodies were increased. Inversely, the mitotic bodies increased in group II animals and reduced in group III, IV, and V animals. In the colonic section, DMH-induced cancer assay exhibited significant effects on the levels of hemoglobin, Packed cell volume (PCV), Red blood cell (RBC) counts, Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), and Mean cell hemoglobin (MCH), and was found to be less in group II animals whereas administration of C. reflexa efficiently recovered back the loss probably by healing the colon damage/depletion of cancer progression. Moreover, compared to the group II animals, the neutrophil count was within the normal range in C. reflexa administered group. In the present study, the major hematological parameters significantly increased within DMH treated animals and exhibited extensive damage in the hepatic regions. Moreover, the histopathological findings demonstrated that the C. reflexa extracts potentially reduced the cell proliferation, with no toxicity. The C. reflexa extracts exhibited impending anti-cancer activity as well as protected the hepatic cells and thus could be potentially used in the management of colon or colorectal cancer and hepatic impairments. [Display omitted] • Cuscuta Reflexa Roxb. treated animals showed improved results in hepato-specified factors. • Histopathological parameters were significantly improved in C. reflexa treated animals. • Animals given C. reflexa showed a probable reduction in tumor progression, which signifies its anti-colon cancer activity. • C. reflexa treated animals exhibited negligible toxicity in the hepatic environment. [ABSTRACT FROM AUTHOR]

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10–15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed. [ABSTRACT FROM AUTHOR]