Compound 1l Research Articles

Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4–6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure–activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund’s adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1–100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.

Benzodioxane Carboxamide Derivatives As Novel Monoamine Oxidase B Inhibitors with Antineuroinflammatory Activity.

In this study, a series of N-phenyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide derivatives were designed, synthesized, and evaluated for their inhibitory activities against human MAO-B (hMAO-B). The structure-activity relationship (SAR) was investigated and summarized. Compound 1l (N-(3,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide) showed the most potent inhibitory activity with an IC50 value of 0.0083 μM and the selectivity index (IC50 (hMAO-A)/IC50 (hMAO-B)) was >4819. Kinetics and reversibility studies confirmed that compound 1l acted as a competitive and reversible inhibitor of hMAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions, and the rationale was provided. Additionally, compound 1l could effectively inhibit the release of NO, TNF-α, and IL-1β in both LPS- and Aβ1-42-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ1-42. Since compound 1l exhibited low neurotoxicity, we believe that the hit compound with dual activities of inhibiting MAO-B and antineuroinflammation could be further investigated as a novel potential lead for future studies in vivo.

Unveiling the potential of novel indol-3-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors: a combined in silico, synthesis and in vitro study.

Considering the failure of many enzyme inhibitors for Alzheimer's disease (AD), research is now focused on multi-target directed drug discovery. In this paper, inhibition of two essential enzymes implicated in AD pathologies, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), has been explored. Taking clues from our previous work, 41 novel indol-3-yl phenyl allylidene hydrazine carboximidamide derivatives were synthesized. The results indicated that compounds inhibited both enzymes in micromolar concentrations. Compound 1l is proposed as the most active. In silico, it was seen to occupy the binding pocket of AChE and BACE 1. The ADME predictions showed that these compounds have acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and BACE 1 dual inhibition as a promising strategy for AD treatment.

Semi-Synthesis of Flavonoid Glycosides and Their Anti-Inflammatory and Antitumor Activities towards Triple Negative Breast Cancer.

Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti-inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields. In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti-inflammatory activities of these compounds. A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti-inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) production in LPS-induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, 1 H-NMR, and 13 C-NMR, and their cytotoxicity on the human triple-negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay. Most of the compounds markedly reduced NO production in LPS-stimulated murine macrophages at the tested concentrations in a dose-dependent manner. Among these, compounds 1, 7, 9, and 17 showed significant anti-inflammatory activities against NO production in LPS-induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF-α and IL-6 in a concentration-dependent manner. Most of the tested compounds showed remarkable anti-human TNBC activities. Compounds 1b-1m, 1, and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC50 values were all below 16.61 μM. In addition, compound 1l was the most cytotoxic with IC50 values of 1.38±0.31 μM, while the other compounds were inactive with inhibition rates <50 % at the highest concentration tested (20 μM). A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 μM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.

Photoluminescent supramolecular gels derived from phenylenediamine hydrochlorides.

Supramolecular gels are promising as chemosensors, drug delivery systems and oil gelators. The present paper deals with photoluminescent supramolecular gels derived from phenylenediamine hydrochlorides. N-(3,5-Diaminobenzoyl)-L-alanine dodecyl ester dihydrochlorides (1L) underwent gelation in tetrahydrofuran (THF) and CHCl3, but not in C1-C4 alcohols, dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF). Compound 1L emitted blue fluorescence in the sol state and green fluorescence in the gel state. A THF solution of 1L exhibited absorption and emission maxima at wavelengths 94-104 nm and 92-110 nm longer than those in other solvents, such as methanol and ethanol, that cause no gelation of 1L. Particles with hydrodynamic diameters around 13 nm were detected in a THF solution (c = 1.0 mM) of 1L. The gelation of 1L in THF and CHCl3, and the lack of gelation in MeOH were supported by molecular dynamics simulations and dynamic light scattering measurements. N-(3,5-Diaminobenzoyl)-L-alanine dodecyl ester (1L'), an HCl-free analogous compound of 1L, underwent no gelation in THF and CHCl3, indicating the necessity of the ammonium salt structure for gelation. The UV-vis absorption and photoluminescence spectroscopic peaks of 1L red-shifted upon aggregation, which was supported by TD-DFT calculations of monomeric and dimeric models of 1L.

Synthesis and Biological Evaluation of Novel Pyrimidine Amine Derivatives Bearing Bicyclic Monoterpene Moieties.

A series of novel pinanyl pyrimidine amine derivatives (1e~1n) and camphoryl pyrimidine amine derivatives (2b~2f) bearing bicyclic monoterpene moieties were designed and synthesized from natural and renewable nopinone and camphor. All chemical structures of target compounds were characterized by 1H NMR, 13C NMR and HRMS spectra analyses, and the antimicrobial activities were evaluated. The results indicated that most compounds showed considerable antibacterial and antifungal activities against Klebsiella pneumoniae, Streptococcus pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Methicillin-Resistant Staphylococcus aureus (MRSA), Bacillus cereus and Candida albicans. Among them, 1f showed potent antibacterial activity against all tested bacteria, 1i exhibited excellent inhibition against Streptococcus pneumoniae (1 μg/mL) and Escherichia coli (1 μg/mL), which was better than the control drug amikacin (2 μg/mL). As to antifungal activity against Candida albicans (C. albicans), compound 1l showed comparable activity (16 μg/mL) to the control drug ketoconazole. Furthermore, five active compounds with better antimicrobial activities also showed anti-inflammatory potencies against mouse mononuclear macrophages leukemia cells (RAW). Especially, 1f (IC50 = 1.37 μM) and 2f (IC50 = 1.87μM) are more potent than the control drug aspirin (IC50 = 1.91 μM).

Design and synthesis of new quinoline derivatives as selective C-RAF kinase inhibitors with potent anticancer activity

This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI50 and total growth inhibition (TGI) values against the cell lines. Three of the tested molecules exerted higher potency against most of the cell lines than the reference drug, sorafenib. Compound 1l indicated a higher potency than sorafenib against 53 of tested cancer cell lines. Compounds 1j-l demonstrated promising selectivity against cancer cells than normal cells. Moreover, compound 1l induced apoptosis and necrosis in RPMI-8226 cell line in a dose-dependent manner. In addition, compounds 1j-l were tested against C-RAF kinase as a potential molecular target. The three compounds showed high potency, and the most potent C-RAF kinase inhibitor was compound 1j with an IC50 value of 0.067 μM. In addition, Compounds 1j-l were further tested at 1 μM concentration against a panel of another twelve kinases and they showed a high selectivity for C-RAF kinase. Molecular modeling studies were performed to illuminate on the putative binding interactions of these motifs in the active site of C-RAF kinase. Additional studies were conducted to measure aqueous solubility, partition coefficient, and Caco-2 permeability of the most promising derivatives.

Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents.

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80±0.04μM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50=0.55±0.01μM). Furthermore, invitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50=4.70±0.67μM), and 1h (IC50=1.58±0.20μM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.

Design, synthesis, molecular docking, anti-proliferative and anti-TB studies of 2H-chromen-8-azaspiro[4.5]decane-7,9-dione conjugates

In this work, a series of new 8-[(substituted 2-oxo-2H-chromen-4-yl)methyl]-8-azaspiro[4.5]decane-7,9-dione derivatives (1a - 1l) is synthesized and characterized by 1H NMR, 13C NMR, FT-IR, GC-MS and elemental analysis. In addition, the structure of compound 1k has been elucidated using single crystal X-ray diffraction techniques. The synthesized compounds are screened for their anticancer and anti-TB activity. Preliminary anticancer results showed that compounds (1a- 1l) exhibit moderate to potent activity against MDA-MB-231, A549, HT-29 and Hela cancer cell lines. Compound 1f exhibited the most potent activity against MDA-MB-231cell line with IC50 value of 9.05 µM concentration, compound 1g and 1h showed potent activity against A549 cell line with IC50 value of 7.05 and 13.31 µM concentration respectively. Compound 1j showed good cytotoxicity against Hela cell line with IC50 of 16.14 µM, whereas, compound 1l is found to be moderately active against HT-29 cell line with IC50 of 18.07 µM. Anti-tubercular activity revealed that compound 1c, 1d, 1g, 1h and 1j have significant activity against MTBH37Rv strain with MIC 0.78, 1.56, 0.19, 0.39 and 0.78 µg/mL respectively. Further, to investigate the mechanism of anti-TB activity and detailed intermolecular interactions between the synthesized compounds, molecular docking studies are performed.

New Antiparasitic Bis-Naphthoquinone Derivatives.

A series of bis-naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a, 3,4-difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5-trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.

Fertilizantes foliares, regulador de crescimento e glyphosate no crescimento vegetativo da soja tolerante ao glyphosate

The present work has the objective of measure the performance of the soybean submitted to doses of glyphosate, as well as the association of products to the herbicide, aiming the process of reversion of the phytotoxic effect in soybean RR2. The experiment was conducted in November of 2015 to January of 2016, in a greenhouse at the Federal University of Parana - Palotina Sector. The cultivar was a Monsoy 6210 IPRO® in a completely randomized design with four replicates. Plants were submitted to the herbicide glyphosate in a dose of 0, 720, 1440, 2160 and 2880 g a.e. ha -1 and doses of glyphosate in combination with the products growth regulator, in a dose of 250ml ha-1,manganese and a aminoacids compound (1L ha-1) Plant chlorophyll index, dry matter of roots and aerial part, and visual note of phytotoxicity was evalueted, which was determined by assigning notes representing a percentage of damaged leaf area. The data were submitted to a variance analysis and a test of rate comparation was used (Tukey) and were submitted to a linear regression test for the dose test (p≤0.05). It was observed that in the cultivar adopted, in its circumstances of this experiment, the manganese and the growth regulator were effective in the evaluation of the visual note of phytointoxication. In dry mass of roots and aerial part there was no significant difference between treatments.

Synthetic Optimization of Ellipticine and Antitumor Activity of Novel Hexacyclic Derivatives of Ellipticine.

For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application. A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated. The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity. Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 μM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.

Preparation and properties of a coniferin enantiomer

l-Coniferin (1L), which is an enantiomer of natural coniferin (d-coniferin (1D)), was prepared from l-glucose according to the conventional method for compound 1D. The reactivity of l-glucose and its derivatives was found to be almost same as that of the corresponding d-glucose and its derivatives during the preparation for compound 1L. Compound 1L showed resistance toward enzymatic hydrolysis by commercial β-glucosidase from Almond. However, unlike compound 1D, compound 1L was not transported across the membrane obtained from differentiating xylem of a hybrid poplar in the present assay. The result suggested for the first time that the d-/l-configuration of the glucose moiety of coniferin is an important factor affecting coniferin transport across the membrane.

Thermally activated delayed fluorescence in dibenzothiophene sulfone derivatives: Theory and experiment

The photophysical properties are calculated for the dibenzothiophene sulfone substituted with various electron donor moieties:3,7-bis[N,N-di(4-tert-butylphenyl)amino]dibenzothiophene-S,S-dioxide (1L), 2,8-bis[N,N-di(4-tert-butylphenyl)amino]dibenzothiophene-S,S-dioxide (1A), and 2,8-bis[N,N-di(4 methoxyphenyl)amino]dibenzothiophene-S,S-dioxide (2A). It is shown that the linear arrangement of the electron donor substituents relative to the dibenzothiophene sulfone acceptor turns compound (1L) an efficient prompt fluorescent emitter, while the angular arrangement of the substituents decreases the efficiency of prompt fluorescence, but increases the efficiency of thermally activated delayed fluorescence (TADF). Replacing the auxiliary tert-butyl groups in the donor moieties by methoxy groups leads to an increase in kISC and kRISC. OLEDs are made with the studied compounds.

Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives

Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compounds were investigated for their anti-inflammatory activity by inhibiting interleukin-1β (IL-1β), interleukin-6 (IL-6) and production of nitric oxide (NO) in mouse RAW264.7 macrophages, and the structure-activity relationship of them was discussed. Among them, the compound 1l, 2c demonstrated more effective inhibitory activity of IL-1β and IL-6, meanwhile, the compound 1l showed the best inhibition of NO production. The results of NO inhibition study were basically accord with the molecular docking results of inducible nitric oxide synthase (iNOS). Furthermore, the expression of LPS-induced iNOS and components of NF-κB signaling pathway were reduced by compound 1l. Our results suggest that the inhibitory effect of compound 1l on LPS-stimulated inflammatory mediator production in RAW 264.7 cells is associated with the suppression of NF-κB signaling pathway and inhibition of iNOS protein and iNOS activity. From in vivo study, it was also observed that compound 1l had hepato-protective and anti-inflammatory effects in CCl4-induced acute liver injury mouse models.

Novel synthetic chalcones induce apoptosis in the A549 non-small cell lung cancer cells harboring a KRAS mutation

A series of novel chalcones were synthesized by the Claisen-Schmidt condensation reaction of tetralones and 5-/6-indolecarboxaldehydes. Treatment of human lung cancer cell line harboring KRAS mutation (A549) with the chalcones induced dose-dependent apoptosis. Cell cycle analyses and Western blotting suggested the critical role of the chalcones in interrupting G2/M transition of cell cycle. SAR study demonstrated that substituent on the indole N atom significantly affects the anticancer activity of the chalcones, with methyl and ethyl providing the more active compounds (EC50: 110–200nM), Compound 1g was found to be >4-fold more active in the A549 cells (EC50: 110nM) than in prostate (PC3) or pancreatic cancer (CLR2119, PAN02) cells. Furthermore, compound 1l selectively induced apoptosis of lung cancer cells A549 (EC50: 0.55μM) but did not show measurable toxicity in the normal lung bronchial epithelial cells (hBEC) at doses as high as 10μM, indicating specificity towards cancer cells.

Synthesis, Structure Activity Relationship (SAR), and Biological Activities of Benzylideneacetophenones Derivatives

Oxygen has double-edge properties as it is essential for life, but can also provoke oxidative stress by protein & lipid per oxidation. The persistent oxidative stress and excess LPO induce several inflammatory mediators such as prostaglandins and leuckotrienes by activating enzymes cyclooxygenase and lipoxygenase. The per oxidation can be blocked by free radical scavengers as antiinflammatory agents. Most of the anti-inflammatory agents, which inhibit the above mentioned enzymes, are associated with side effects such as ulceration and bleeding in gastrointestinal tract; so the attention is focused on benzylideneacetophenones having antinflammatory, antioxidant and gastric protectant activities by virtue of free radical scavengers. A systematic analysis of the structural features responsible for biological activities and a possible mode of their actions were proposed to be evaluated by synthesizing a set of compounds, screening them for anti-inflammatory, antioxidant and antiulcer activity. The benzylideneacetophenones derivatives were synthesized employing the Claisen-Schmidt condensation. The structure of the compounds were established by IR, (1)H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (carrageenan-induced rat paw edema assay), antioxidant (inhibition of lipid peroxidation) and antiulcer activity (indomethacin-induced gastric damage). Possible correlation between observed biological activities and substituents at different positions on rings was also studied. The data revealed that compounds 1e, 1m and 1l showed equivalent activity to indomethacin (reference drug) at the fourth hour at dose of 100 mg/kg. Among the tested compounds 1m & 1l exhibited the highest lipid per oxidation inhibitory activity (IC50 2.38µg/ml, 3.08 µg/ml) followed by 1i, 1h, 1e. In addition, all compounds at the tested dose level (100mg/kg, p.o.) exhibited varying degree of activity against ulceration induced by indomethacin. The compounds 1m, 1l, 1e, and 1i showed excellent activity (71-75%), whereas compounds 1d, 1h and 1j exhibited good to moderate (60-69%) activity. SAR analysis revealed that presence of electron donating groups on p- position of both rings A and B seems to enhance anti-inflammatory, antioxidant and antiulcer activity. The compound 1m (4-amino-4'-ethoxychalcone) and 1l (4-amino-4'-methoxychalcone) have equivalent antiinflammatory activity in comparison with the reference drug. Moreover, the same compounds also obtained promising antioxidant and antiulcer activities. Thus, I m could be explored further for development of potent anti inflammatory agent.

In-silico design, synthesis and biological evaluation of 4-aryl-4H-chromene derivatives as CDK-2 inhibitors: A molecular approach to finding a lead for breast cancer

Breast cancer is a major health concern, with a mortality rate worldwide. Targeted therapy has emerged as a promising option for cancer treatment, particularly through the inhibition of cyclin-dependent kinase-2 (CDK-2), holding a promise for combating this disease. The potential of 4-aryl-4H-chromene derivatives as inhibitors of CDK- 2 was evaluated in this study using the in silico method. Amongst the 38 designed compounds, 13 compounds were identified as potential CDK-2 inhibitors based on their superiority within in silico studies with docking scores ranging from −9.180 to −8.006 Kcal/mol and with favourable absorption, distribution, metabolism, excretion, and toxicity properties. These 13 compounds were later synthesized and characterized using spectral methods. Furthermore, these compounds were assessed for their antioxidant and anticancer properties by in vitro assays. Compounds 2M and 2C displayed notable antioxidant potential with IC50 values of 24.44 and 39.03 μM, respectively, in 2,2-Diphenyl- 1-picrylhydrazyl and 2,2′-casino-bis (3-ethylbenzothiazoline-6-sulfonic acid) assays. The sulforhodamine B assay on Michigan Cancer Foundation-7 (MCF-7) cells indicated that compound 1L demonstrated the strongest growth inhibition activity with an IC50 of 0.2 μM. Five other compounds (2O, 2K, 1C, 2M, and 2J) also exhibited promising activity with IC50 values ranging from 11.74 to 27.2 μM. In conclusion, 4-aryl-4H-chromene derivatives can be considered potential lead candidates for breast cancer treatment.

Development of hypoxia-inducible factor (HIF)-1α inhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia

A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI50) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC50: 1.9±0.4 and 1.4±0.2μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC50: 6.80±0.25μM) and this inhibition activity was higher than that of ETB (IC50: 10.9±0.63μM).

Design, synthesis and structure–activity relationship of novel inhibitors against H5N1 hemagglutinin-mediated membrane fusion

We reported previously that a small molecule named CL-385319 could inhibit H5N1 influenza virus infection by targeting hemagglutinin, the envelope protein mediating virus entry. In the present study, a novel series of derivatives focused on the structural variation of CL-385319 were synthesized as specific inhibitors against the H5 subtype of influenza A viruses. These small molecules inhibited the low pH-induced conformational change of hemagglutinin, thereby blocking viral entry into host cells. Compound 1l was the most active inhibitor in this series with an IC50 of 0.22 μM. The structure–activity relationships analysis of these compounds showed that the 3-fluoro-5-(trifluoromethyl)benzamide moiety was very important for activity, and the –F group was a better substituent group than –CF3 group in the phenyl ring. The inhibitory activity was sensitive to the benzamide because the oxygen and hydrogen of the amide served as H-bond acceptor and donor, respectively.