Compounds 4l Research Articles

Click synthesis, antimicrobial, DNA photocleavage and computational studies of oxindole-tethered 1H-1,2,3-triazoles.

Aim: To obtain new hybrids derived from isatin and triazole. Materials & methods: A series of oxindole-1-H-1,2,3-triazole hybrids (4a-l) were synthesized from 3-sulfenylated N-propargylated oxindoles and organic azides employing Cu(I)-catalyzed azide-alkyne cycloaddition. These compounds were evaluated in vitro for antimicrobial activity by the standard serial dilution method and DNA photocleavage activity. Results: Antimicrobial assay revealed that compounds 4l and 4f exhibited promising efficacy against Candida albicans and Rhizopus oryzae, respectively, with aminimum inhibitory concentrationvalue of 0.0008μmol/mL. Compounds 4h and 4k completely degraded plasmid DNA. Further molecular docking of compounds with 1KZN (4j and 4k) and 5TZ1 (4h and 4l) revealed good binding interactions. Conclusion: Results of the current research can help in the development of new antimicrobial agents with high efficacy.

Synthesis and Molecular Docking Studies of Novel Biheterocyclic Propanamides as Antidiabetic Agents Having Mild Cytotoxicity.

The aim of this work was to bring forth some new hybrid molecules having pharmacologically potent indole and 1,3,4-oxadiazole heterocyclic moieties unified with a propanamide entity. The synthetic methodology was initiated by esterification of 2-(1H-indol-3-yl)acetic acid (1) in a catalytic amount of sulfuric acid and ethanol in excess, to form ethyl 2-(1H-indol-3-yl)acetate (2), which was converted to 2-(1H-indol-3-yl)acetohydrazide (3) and further transformed to 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). 3-Bromopropanoyl chloride (5) was reacted with various amines (6a-s) in aqueous alkaline medium to generate a series of electrophiles, 3-bromo-N-(substituted)propanamides (7a-s), and these were further reacted with nucleophile 4 in DMF and NaH base to yield the targeted N-(substituted)-3-{(5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl)sulfanyl}propanamides (8a-s). The chemical structures of these biheterocyclic propanamides were confirmed by IR, 1H NMR, 13C NMR, and EI-MS spectral techniques. These compounds were evaluated for their enzyme inhibitory potentials against the α-glucosidase enzyme, where the compound 8l showed promising enzyme inhibitory potential with an IC50 value less than that of the standard acarbose. Molecular docking results of these molecules were coherent with the results of their enzyme inhibitory potentials. Cytotoxicity was assessed by the percentage of hemolytic activity method, and these compounds generally exhibited very low values as compared to the reference standard, Triton-X. Hence, some of these biheterocyclic propanamides might be considered as salient therapeutic agents in further stages of antidiabetic drug development.

Design and Synthesis of Novel Oxathiapiprolin Derivatives as Oxysterol Binding Protein Inhibitors and Their Application in Phytopathogenic Oomycetes.

Oomycetes, particularly those from the genus Phytophthora, are significant threats to global food security and natural ecosystems. Oxathiapiprolin (OXA) is an effective oomycete fungicide that targets an oxysterol binding protein (OSBP), while the binding mechanism of OXA is still unclear, which limits the pesticide design, induced by the low sequence identity of Phytophthora and template models. Herein, we generated the OSBP model of the well-reported Phytophthora capsici using AlphaFold 2 and studied the binding mechanism of OXA. Based on it, a series of OXA analogues were designed. Then, compound 2l, the most potent candidate, was successfully designed and synthesized, showing a control efficiency comparable to that of OXA. Moreover, field trial experiments showed that 2l exhibited nearly the same activity (72.4%) as OXA against cucumber downy mildew at 25 g/ha. The present work indicated that 2l could be used as a leading compound for the discovery of new OSBP fungicides.

Design and synthesis of novel 1,2,4-triazolo[4,3-b]pyridazine derivatives with anti-cancer activity

Novel 1,2,4-triazolo[4,3-b]pyridazine derivatives (7a–d, 8a–m and 9a–i) were designed and synthesized in good to moderate yields. The synthesized compounds were characterized by spectroscopic studies (NMR and IR) and the fluorine coupled 13C NMR data for each synthesized series have also been explained. The compounds were evaluated for their in-vitro anti-proliferative activity against K562, MV4-11, G361 and HCC827 human cancer cell lines. Almost all the synthesised compounds were active against MV4-11 below 25 µM, especially 8l which showed activity with IC50 of 1.5 µM. Furthermore, compound 8l displayed anticancer activity against all four cancer cell lines tested with IC50 values ranging from 1.5 to 7.6 µM. In general, most of the compounds did not show any significant anti-proliferative activity against K562, G361 and HCC827 cells. Preliminary investigation of their effect on proliferation and viability of MV4-11 cells was carried out with 8l and the results indicate that the cells undergo a cell death with biochemical signs of apoptosis.

Targeting Mycobacterium tuberculosis: Synthesis, in vitro and in silico evaluation of novel N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds.

The development of novel antimycobacterial agents is an urgent challenge to eradicate the increasing emergence and rapid spread of multidrug-resistant strains. Filamentous temperature-sensitive protein Z (FtsZ) is a crucial cell division protein. Alteration of FtsZ assembly leads to cell division inhibition and cell death. To find novel antimycobacterial agents, a series of N1 -(benzo[d]oxazol-2-yl)-N4 -arylidine compounds 5a-o were synthesized. The activity of the compounds was evaluated against drug-sensitive, multidrug-resistant, and extensive-drug-resistant Mycobacterium tuberculosis. Compounds 5b, 5c, 5l, 5m, and 5o showed promising antimycobacterial activity with minimum inhibitory concentrations (MIC) in the range of 0.48-1.85 µg/mL and with low cytotoxicity against human nontumorigenic lung fibroblast WI-38 cells. The activity of the compounds 5b, 5c, 5l, 5m, and 5o was evaluated against bronchitis causing-bacteria. They exhibited good activity against Streptococcus pneumoniae, Klebsiella pneumoniae, Mycoplasma pneumonia, and Bordetella pertussis. Molecular dynamics simulations of Mtb FtsZ protein-ligand complexes identified the interdomain site as the binding site and key interactions. ADME prediction indicated that the synthesized compounds have drug-likeness. The density function theory studies of 5c, 5l, and 5n were performed to investigate E/Z isomerization. Compounds 5c and 5l are present as E-isomers and 5n as an E/Z mixture. Our experimental outcomes provide an auspicious lead for the design of more selective and potent antimycobacterial drugs.

Unexpected Cascade Sequence Forming the C(sp3)-N/C(sp2)-C(sp2) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp3)-N bond and a C(sp2)-C(sp2) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that 7l displayed a high cytotoxicity against HCT116 cells (IC50 = 5.59 ± 0.78 μM). Taken together, our findings revealed new insights into the molecular mechanisms underlying compound 7l and provided potential usage of this scaffold for cancer therapeutics.

Synthesis and investigation of cytotoxic effects of compounds derived from flurbiprofen

New flurbiprofen derivatives containing 1,2,4-triazoline-5-thione (4) and thioethers (5a-r) were synthesized in this study. The structures of synthesized compounds were characterized by spectral methods (FT-IR, 1H NMR, 13C NMR) and 19F NMR (only compound 5l), besides elemental analysis. In addition, molecular binding of these compounds to the human methionine aminopeptidase 2 enzyme was performed using AutoDock 4.2, the software product of the research, computationally. All synthesized compounds were evaluated for cytotoxic effect against MDA-MB231 triple-negative breast cancer cell line by using WST-1 Cell Viability and Proliferation assay. Doxorubicin is in the anthracycline class and is an antineoplastic agent. It is used to provide regression in common neoplastic conditions such as breast carcinoma. Due to the cardiovascular side effects of doxorubicin, a combination study was conducted with the (±)(R,S)-3-{1-[2-fluoro-(1,1′-biphenyl)-4-yl]ethyl}-4-methyl-5-{[2-(trifluoromethyl)benzyl]thio}-4H-1,2,4-triazole (5l) with promising cytotoxic effects. As a result of the combination, it was shown as 7% MDA-MB231 cell viability. Therefore, based on the evaluations, a better cytotoxic effect was achieved with the 5l combination depending on the low dose of doxorubicin.

Synthesis, Antimicrobial, and Antibiofilm Activities of Some Novel 7-Methoxyquinoline Derivatives Bearing Sulfonamide Moiety against Urinary Tract Infection-Causing Pathogenic Microbes.

A new series of 4-((7-methoxyquinolin-4-yl) amino)-N-(substituted) benzenesulfonamide 3(a-s) was synthesized via the reaction of 4-chloro-7-methoxyquinoline 1 with various sulfa drugs. The structural elucidation was verified based on spectroscopic data analysis. All the target compounds were screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and unicellular fungi. The results revealed that compound 3l has the highest effect on most tested bacterial and unicellular fungal strains. The highest effect of compound 3l was observed against E. coli and C. albicans with MIC = 7.812 and 31.125 µg/mL, respectively. Compounds 3c and 3d showed broad-spectrum antimicrobial activity, but the activity was lower than that of 3l. The antibiofilm activity of compound 3l was measured against different pathogenic microbes isolated from the urinary tract. Compound 3l could achieve biofilm extension at its adhesion strength. After adding 10.0 µg/mL of compound 3l, the highest percentage was 94.60% for E. coli, 91.74% for P. aeruginosa, and 98.03% for C. neoformans. Moreover, in the protein leakage assay, the quantity of cellular protein discharged from E. coli was 180.25 µg/mL after treatment with 1.0 mg/mL of compound 3l, which explains the creation of holes in the cell membrane of E. coli and proves compound 3l's antibacterial and antibiofilm properties. Additionally, in silico ADME prediction analyses of compounds 3c, 3d, and 3l revealed promising results, indicating the presence of drug-like properties.

Design and synthesis of pseudo-rutaecarpines as potent anti-inflammatory agents via regulating MAPK/NF-κB pathways to relieve inflammation-induced acute liver injury in mice

Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1β and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives as potential inhibitors of TNF-α

'The anti-inflammatory activities of the 2,3-dihydroquinazolin-4(1H)-one derivatives along with results from our in silico predictions (this study) encouraged us to explore this class of compounds as potential inhibitors of TNF-α. Among all the molecules assessed in silico the best ranked molecules were identified with the order as 3h > 3p > 3l based on the estimated total energy. The compound 3h participated in a H-bond interaction through its C = O group of the quinazoline-4(1H)-one ring with TYR151 of chain A in addition to the interactions with all the critical TYR residues via its chloro group. The interesting docking results were also obtained for compound 3l and 3p. For the access of this class of fused N-heteroarenes we adopted the β-cyclodextrin (β-CD) catalyzed approach involving the cyclocondensation of 2-aminobenzamide with aldehydes / ketones in pure water. Various aromatic, aliphatic and heteroaromatic aldehydes (including the cinnamaldehyde) along with ketones were employed for this purpose to afford the corresponding product in good to excellent yield. The recovery and recycling of the catalyst β-CD was successful. The inexpensive and eco-friendly nature along with the simple product purification as well as good product yield are the key advantages of this approach. When examined in vitro the compound 3h, 3l and 3p with the inhibition > 70% emerged as the most active compounds in this series as predicted by in silico studies. According to the SAR (Structure Activity Relationship) the effectiveness of the C-2 aryl group was found to be in the order Ar = C6H4Cl-p > 4-pyridyl > C6H4OMe-p > C6H2(OMe)3-m,p > C6H4OH-p etc. whereas an heteroaryl or alkyl group at this position was found to be less effective or ineffective. In terms of IC50 values the compound 3h, 3l and 3p appeared as superior than the known inhibitor thalidomide though they were not better than rolipram. Being identified as preliminary hits these compounds are of further pharmacological interest.

Design, synthesis, antimicrobial activity, DFT, and molecular docking studies of pyridine-pyrazole-based dihydro-1,3,4-oxadiazoles against various bacterial and fungal targets.

Antimicrobial resistance which is increasing at an alarming rate is a severe public health issue worldwide. Hence, the development of novel antibiotics is an urgent need as microbes have developed resistance against available antibiotics. In search of novel antimicrobial agents, a convenient route for the preparation of substituted 3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-1-(2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)prop-2-en-1-ones (6a-6o) has been adopted by using pyridine-3-carbohydrazide and various aromatic aldehydes. The newly synthesized compounds were characterized by using various spectral techniques, for example, IR, 1 H NMR, 13 C NMR, and mass spectroscopy. Synthesized hybrids were studied for in vitro antimicrobial potency against various bacterial and fungal strains. Antibacterial results revealed that compounds 6e, 6h, 6i, 6l, and 6m were found to be most active against bacterial strains as they showed minimum inhibitory concentration(MIC) value of 62.5 μg/mL while compounds 6d, 6e, and 6h showed MIC value of 200 μg/mL against Candidaalbicans. The quantum parameters that relate to the bioavailability of the compounds were computed, followed by docking with different bacterial and fungal targets like sortase A, dihydrofolate reductase, thymidylate kinase, gyrase B, sterol 14-alpha demethylase. The experimental and computational results are in good agreement.

Design, Synthesis and In Vitro Studies of 3-Amidocoumarins as Novel Antibiofilm Agents

Pseudomonas aeruginosa, a life-threatening bacteria listed as a priority pathogen by World Health Organization WHO, is known to cause severe nosocomial infections and fatality in immunocompromised individuals through its quorum sensing (QS) mediated biofilm formation. P. aeruginosa’s antibiotic-resistant biofilms are highly challenging to the existing antibiotic treatment options. There is an urgent clinical need to develop novel alternative therapeutic molecules such as antibiofilm and antiquorum sensing agents to counter the emergence of an unprecedented pace of antibiotic resistance of pathogens. In this context, a library of seventy 3-amidocoumarin derivatives was designed, and docking studies were performed against the P. aeruginosa LasR receptor using AutoDock 4.0. Based on docking results, a final series of sixteen 3-amidocoumarin derivatives (4a–p) were synthesized and evaluated for antibiofilm activity in vitro. Eight compounds significantly inhibited the formation of P. aeruginosa PAO1 biofilm. Compounds 4f, 4l and 4o showed maximum % inhibition in antibiotic-resistant P. aeruginosa PAO1 biofilm formation in the range of 80% to 86%. Further, the structure–activity relationship (SAR) studies revealed that the presence of electron-donating and bromo substituents at benzamido and coumarin moieties, respectively, effectively enhances the antibiofilm activity. In addition, the binding interactions between the synthesized compounds and active sites of the LasR QS receptor (Protein Data Bank Code: 2uv0) in P. aeruginosa were also investigated by molecular docking. The high binding affinities indicate that these compounds might be suitable for development into potent inhibitors of QS and biofilm disruptors.

Synthesis, in vitro α-glucosidase inhibitory activities, and molecular dynamic simulations of novel 4-hydroxyquinolinone-hydrazones as potential antidiabetic agents

In the present study, new structural variants of 4-hydroxyquinolinone-hydrazones were designed and synthesized. The structure elucidation of the synthetic derivatives 6a–o was carried out using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, and elemental analysis, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 6a–o exhibited good α-glucosidase inhibition with IC50 values ranging between 93.5 ± 0.6 to 575.6 ± 0.4 µM as compared to the standard acarbose (IC50 = 752.0 ± 2.0 µM). Structure–activity relationships of this series were established which is mainly based on the position and nature of the substituent on the benzylidene ring. A kinetic study of the active compounds 6l and 6m as the most potent derivatives were also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of the enzyme were determined by molecular docking and molecular dynamic simulations.

Design, Synthesis, and Investigation of Cytotoxic Effects of 5-Hydroxyindole-3-Carboxylic Acid and Ester Derivatives as Potential Anti-breast Cancer Agents.

Breast cancer is a deadly disease with a high prevalence rate among females. Despite several treatments, scientists are still engaged in finding less invasive treatments for this disease. The cellular proliferation rate and cell viability survey are critical to assess the drug's effect on both normal and malignant cell populations. Indole derivatives are promising candidates for their cytotoxic effect causing on breast cancer cells; however, they are less toxic on normal cells. This study synthesized 23 novel 5-hydroxyindole-3-carboxylic acids and related esters featuring various linear, cyclic, and primary aromatic amines. The MTT assay indicated the cytotoxicity of all acid and ester derivatives against the MCF-7 cells with no significant cytotoxicity on normal human dermal fibroblasts cells. Compound 5d, an ester derivative possessing a 4-methoxy group, was the most potent compound, with a half-maximal effective concentration of 4.7 µM. Compounds 5a, 5d, and 5l bearing ester group in their structure demonstrated cytotoxicity values < 10 µM against the MCF-7 cell line and were safe for advanced screening.

Synthesis and Antifungal Activity of Derivatives of the Natural Product Griseofulvin against Phytopathogenic Fungi.

Natural products are important sources for the discovery of new pesticides. Chemical synthesis and structural modification can lead to pesticides. Despite abundant research in fungicide discovery for crop protection, there is an emerging need for the development of novel antifungal agrochemicals. Herein, 39 diversified griseofulvin derivatives were effectively synthesized from the natural product griseofulvin by diversity-oriented synthesis through the reactions of demethylation, ammonolysis, methylation, nitration, acylation, reduction, and chlorination. Among them, 31 derivatives were novel. All structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HR-MS), and the antifungal activity was investigated against five phytopathogenic fungi. Compounds 5h and 5l had excellent activity against Botrytis cinerea (5h, IC50 = 17.29 ± 0.64 μg/mL) and Alternaria solani (5l, IC50 = 22.52 ± 0.79 μg/mL), respectively. Compound 9 exhibited the more promising activities against three target fungi, especially against Colletotrichum gloeosporioides (IC50 = 7.24 ± 0.66 μg/mL), which is obviously better than positive control hymexazol, thifluzamide, and parent compound griseofulvin. In addition, compound 10 showed significant and extensive activities against four target fungi Cytospora sp. (IC50 = 18.72 ± 0.35 μg/mL), C. gloeosporioides (IC50 = 31.39 ± 1.48 μg/mL), A. solani (IC50 = 40.82 ± 1.04 μg/mL), and Fusarium solani (IC50 = 36.81 ± 0.82 μg/mL). Unexpectedly, 11 and 12, the chlorinated products of compound 9, exhibited the most promising activity against C. gloeosporioides (IC50 = 4.48 ± 0.54 μg/mL for 11, 2.24 ± 0.76 μg/mL for 12). Furthermore, 12 showed remarkable activity against Cytospora sp. (IC50 = 5.85 ± 0.72 μg/mL). Additionally, in vivo antifungal activity against C. gloeosporioides, homology modeling, and docking analysis of 11, 12, and griseofulvin were conducted. All results indicated that 11 and 12 had potency as antifungal agents against C. gloeosporioides, and the modifications of the 2' and 4' positions of griseofulvin should be further explored for higher-activity lead compounds or potential agricultural fungicides.

Design, Synthesis, and Antifungal/Antioomycete Activity of Thiohydantoin Analogues Containing Spirocyclic Butenolide.

Novel fungicidal agents were designed based on the combination of two privileged scaffolds, thiohydantoin and spirocyclic butenolide, which are widely found in natural products. The synthesized compounds were characterized by 1H NMR, 13C NMR, and high-resolution electrospray ionisation mass spectrometry. The in vitro antioomycete activity evaluation showed that most of the compounds exhibited excellent inhibitory activities against different developmental stages in the life cycle of pathogenic oomycete Phytophthora capsici. Compound 5j could inhibit the mycelial growth, sporangium production, zoospore release, and cystospore germination significantly with EC50 values of 0.38, 0.25, 0.11, and 0.026 μg/mL, respectively. The in vivo antifungal/antioomycete bioassay results revealed that the series of compounds generally showed outstanding control efficacies against the pathogenic oomycete Pseudoperonospora cubensis, and compounds 5j, 5l, 7j, 7k, and 7l possessed broad-spectrum antifungal activities against the test phytopathogens. The in vivo protective and curative efficacies against P. capsici of the representative compound 5j were excellent, which were better than those of azoxystrobin. More prominently, 5j significantly promoted the biomass accumulation of the root system and reinforced the cell wall by callose deposition. The pronounced upregulation of immune response-related genes indicated that the active oomycete inhibitor 5j also functioned as a plant elicitor. Transmission electron microscopy observation and the enzyme activity test demonstrated that the mechanism of action of 5j was to bind to the pivotal protein, complex III on the respiratory chain, which resulted in a shortage of energy supply. Molecular docking results exhibited that compound 5j appropriately matched with the Qo pocket and had no interaction with the most commonly mutated site Gly-142, which may be of significant benefit in Qo fungicide resistance management. Compound 5j showed great advantages and potential in oomycete control, resistance management, and induction of disease resistance. A further investigation of 5j with a unique structure might have direct implications for the creation of novel oomycete inhibitors against plant-pathogenic oomycetes.

Structure-based discovery of potent USP28 inhibitors derived from Vismodegib

Ubiquitin-specific proteases (USPs) 28 is overexpressed in multiple types of cancers. The development of potent USP28 inhibitors is still in primitive stage. We previously reported our discovery of Vismodegib as a USP28 inhibitor by screening a commercially available drug library. Herein, we report our efforts to solve the cocrystal structure of Vismodegib bound to USP28 for the first time and subsequent structure-based optimization leading to a series of Vismodegib derivatives as potent USP28 inhibitors. Based on the cocrystal structure, elaborative SARs exploration was carried out to afford much more potent USP28 inhibitors than Vismodegib. The representative compounds 9l, 9o and 9p bearing high potency on USP28 showed high selectivity over USP2, USP7, USP8, USP9x, UCHL3 and UCHL5. The detailed cellular assay suggested that compounds 9l, 9o and 9p could cause cytotoxicity in both human colorectal cancer and lung squamous carcinoma cells and significantly enhance the sensitivity of colorectal cancer cells to Regorafenib. Further immunoblotting analysis indicated that compounds 9l, 9o and 9p could dose-dependently down-regulate the cellular level of c-Myc through ubiquitin-proteasome system and anti-cancer effects could mainly be attributed to their inhibition on USP28 but not involving the Hedgehog-Smoothened pathway. Thus, our work provided a series of novel and potent USP28 inhibitors derived from Vismodegib and may contribute to the development of USP28 inhibitors.

Design, synthesis, α‐glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole‐carbohydrazide‐phenoxy‐N‐phenylacetamide derivatives

A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were designed, synthesized, and screened for their α-glucosidase inhibitory abilities and cytotoxic effects. The results obtained in the α-glucosidase inhibition assay indicated that most of the synthesized derivatives displayed good to moderate inhibitory abilities (Ki values ranging from 14.65 ± 2.54 to 37.466 ± 6.46 μM) when compared with the standard drug acarbose (Ki = 42.38 ± 5.73 μM). Among them, 2-mehoxy-phenoxy derivatives 7l and 7h with 4-nitro and 4-chloro substituents on the phenyl ring of the N-phenylacetamide moiety, respectively, displayed the most inhibition effects. The inhibitory mechanism of these compounds was investigated by molecular docking studies. The in vitro cytotoxicity assay showed that only one compound, 2-methoxy-phenoxy derivative 7k with a 4-bromo substituent on the phenyl ring of the N-phenylacetamide moiety, exhibited moderate cytotoxicity against the human non-small-cell lung cancer cell line A549 and the rest of the compounds show almost no cytotoxicity. Further cytotoxic evaluations were also performed on compound 7k. The in silico pharmacokinetic study predicted that the selected compounds 7l and 7h are likely to be orally active.

One-pot three-component synthesis of novel pyrano[3,2-e]pyrazolo[1,5-a]pyrimidines and investigation of their biological activities

In this study, pyrano[3,2-e]pyrazaolo[1,5-a]pyrimidine derivatives were produced in high yields (80–89%), at room temperature, by three-component reactions involving alkyl isocyanides, dialkyl acetylenedicarboxylates, and 7‑hydroxy pyrazolo[1,5-a]pyrimidines. Using FT-IR, 1H and 13C NMR, and mass spectral data, the structure of the synthesized compounds was identified. The created molecules were tested against cancer, bacteria, and free radicals to evaluate how effective they could be. It was determined whether or not the tested substances had any cytotoxic effects on the MCF-7 (breast cancer) and the MCF-10 (breast epithelial) cell lines. Compound 4l, in comparison to other compounds, has shown the most potent anti-cancer activity (IC50=19.70±0.89 µM), which is roughly as excellent as the standard medicine etoposide (IC50= 18.71±1.09 µM). Also, the antioxidant properties of the products were investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The results demonstrated that compound 4 h had the highest free radical scavenging effect (IC50= 12.12±0.40 µM), which was very close to the value for ascorbic acid (IC50= 11.85±0.30 µM), as the antioxidant standard. The Kirby-Bauer disk diffusion technique was applied to examine the bactericidal impact of the synthesized compounds. According to the findings, virtually all the compounds had a modest level of action against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus).