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Herein, we demonstrate a simple, rapid and green synthesis of 2,4-dimethoxy-THPQs under microwave irradiation and their antiproliferative activity, in silico ADMET and drug-likeness studies were carried out.

Single-crystal XRD analysis of 2,4-dimethoxy THPQs and their relative reactivity with properties were investigated using DFT calculation. Molecular docking studies show they effectively docked with main protease of SARS-CoV-2.

A series of

Herein we report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Upon identification of the anticancer bioactivity of the compound, we carried out structure-activity relationship and rationally designed a library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against murine glioblastoma cell lines and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant brain-penetrant small molecule inhibitors induces enhanced cytotoxicity in a murine glioblastoma cell line. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors.

We report a one-pot two-step synthesis of a bioactive 6-amino-2-pyridone-3,5-dicarbonitrile derivative using natural product catalysts betaine and guanidine carbonate. Anti-cancer bioactivity was observed in specific molecules within the library of 16 derivatives. Out of the compounds, 5o had the most potent anti-cancer activity against glioblastoma cells and was selected for further study. Compound 5o showed anti-cancer properties against liver, breast, lung cancers as well as primary patient-derived glioblastoma cell lines. Furthermore, 5o in combination with specific clinically relevant small molecule inhibitors induced enhanced cytotoxicity in glioblastoma cells. Through our current work, we establish a promising 6-amino-2-pyridone-3,5-dicarbonitrile based lead compound with anti-cancer activity either on its own or in combination with specific clinically relevant small molecule kinase and proteasome inhibitors.

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug-resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacteriumPseudomonas syringae pv syringae.We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer and non-small cell lung cancer lines, effectively inhibit proteasome in primary myeloma cells of refractory patients, and bypass the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating-kinase DYRK2 inhibitor LDN192960. Furthermore, low dose TIR-199 exhibits in vivo activity in delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a next generation drug within the repertoire of proteasome-based therapeutics with a potential to target relapsed and refractory proteasome-addicted neoplasia.

Green synthesis of pyrazolo[3,4-b]quinolinones was designed using bioproduct pyridine-2-carboxylic acid (P2CA) as a green and efficient catalyst. The multi-component reaction of aldehydes, 1,3-cyclodiones and 5-amino-1-phenyl-pyrazoles regioselectively produced pyrazolo[3,4-b]quinolinones in excellent yield (84–98%). Recyclization of the catalyst was also investigated. The electronic effect of the various substituents in aromatic rings indicated that the reaction proceeded through the carbocation intermediate. This newly designed protocol very quickly constructed products conventionally under milder conditions.

Herein, Solvent-free synthesis of 5-bromothiophene based 3,4-dihydropyrimidin-2-(1H)-thi(ones) was explored. The main advantages of this study are that pure product comes in hand with easy workup and without using any separation technique, a good amount of yield, and formation of product in crude form. We developed a single crystal of 4c, and we analysed crystal structure by Hirshfeld surfaces analysis. All the synthesised compounds were screened for antifungal and antibacterial assay. Among all synthesised compounds, 4a, 4b and 4j have potent antibacterial activity. While 4f, 4g, 4h and 4i show good antifungal activity among all synthesised compounds. We also carried out ADMET prediction for the 4(a-j), and calculated data show that all the compounds have prominent drug-like nature.

A series of novel pyrano[2,3-c]pyrazoles were synthesized and screened for their potential to inhibit kinases and exhibit anti-cancer activity against primary patient derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds were evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Herein we establish a novel biochemical kinase inhibitory function for a pyrano[2,3-c]pyrazole derivative and further report its anti-glioma activity in vitro for the first time.

A series of novel pyrano[2,3-c]pyrazoles were synthesized and screened for their potential to inhibit kinases and exhibit anti-cancer activity against primary patient derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds were evaluated against glioma cell lines, with compound 4j exhibiting promising glioma growth inhibitory properties. Compound 4j was screened against 139 purified kinases and exhibited low micromolar activity against kinase AKT2/PKBβ. AKT signalling is one of the main oncogenic pathways in glioma and is often targeted for novel therapeutics. Indeed AKT2 levels correlated with glioma malignancy and poorer patient survival. Compound 4j inhibited the 3D neurosphere formation in primary patient derived glioma stem cells and exhibited potent EC50 against glioblastoma cell lines. Herein we establish a novel biochemical kinase inhibitory function for a pyrano[2,3-c]pyrazole derivative and further report its anti-glioma activity in vitro for the first time.

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 μM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 μM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.

In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and N-substituted 2-cyanoacetamide in the presence of piperidinium acetate as the catalyst. It involved the Knoevenagel condensation of the aldehyde and malononitrile to produce arylidene malononitrile as an intermediate, which was further treated with N-substituted 2-cyanoacetamide to give 6-amino-2-pyridone-3,5-dicarbonitrile derivatives when the less steric bulky group was involved. High steric hindrance changed the earlier reaction route and gave N-substituted 2-cyanoacrylamides via a slower route.

In this study, we successfully explored the effect of steric hindrance on the one-pot reaction of different aryl aldehydes with malononitrile and

A one-pot procedure for the preparation of functionalized 1,4-dihydropyridines by three-component reaction using substituted heterocyclic aldehydes, ammonium acetate, and substituted β-ketoesters catalyzed by L-proline was described. Present protocol offers excellent yield up to 92%, flexibility with different substitution, convenient operation, and eco-friendliness. The synthesized products were confirmed by 1H-NMR, 13C-APT, and IR spectroscopy. Herein, final confirmation of the targeted motif was made by X-ray single-crystal analysis of representative compounds (4f, 4j, 4k, 4l, and 4o). The chemically synthesized compounds were evaluated for the antiproliferative activity by cell viability (MTT) assay and dual AO/EB (acridine orange/ethidium bromide)-staining method against human A549 lung cancer cell lines. The viability of the treated cell was evaluated adopting MTT assay. According to associated changes in cell membranes during the process of apoptosis, a clear difference was observed between normal cells, early and late apoptotic cells, and necrotic cells. All compounds were found effective against Saccharomyces cerevisiae which was confirmed by increased reactive oxygen species production and DNA damage as compared to untreated yeast cell culture. Altogether, these compounds showed promising hope for application in pharmaceutical aid against yeast infections.

Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.