Catalyst-Free, Room-Temperature Accessible Regioselective Synthesis of Spiroquinolines and Their Antioxidant Study.

An efficient, regioselective, and environmentally benign approach was established using the multicomponent reaction-based synthesis of novel antioxidant spiroquinoline derivatives such as spiro[dioxolo[4,5-g]quinoline], spiro[dioxino[2,3-g]quinoline], and spiro[pyrazolo[4,3-f]quinoline] by reaction of aryl aldehyde, Meldrum's acid, and amine derivatives under an additive-free reaction in aqueous ethanol. Here, two asymmetric carbon centers, three new C-C bonds, and one C-N bond are developed in the final motif. This synthetic methodology offers excellent yields with an easy workup procedure, high diastereoselectivity [d.r. >50:1 (cis/trans)], admirable atom economy, and low E-factor values. Synthesized spiro compounds were investigated for their in vitro antioxidant activity by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging assays. In the ABTS radical scavenging assay, compounds 4d, 4f, and 4l exhibit excellent potency, and in the DPPH radical scavenging assay, compounds 4a, 4d, 4f, and 4g, exhibit excellent potency.

Importance of Hybrid Catalysts toward the Synthesis of 5H-Pyrano[2,3-d]pyrimidine-2-ones/2,4-diones (Thiones).

The pyranopyrimidine core is a key precursor for medicinal and pharmaceutical industries due to its broader synthetic applications as well as its bioavailability. Among its four possible isomers, we found that 5H-pyrano[2,3-d]pyrimidine scaffolds have a wide range of applicability, and in recent years, they have been intensively investigated, but the development of the main core is found to be more challenging due to its structural existence. In this review article, we cover all of the synthetic pathways that are employed for the development of substituted 4-aryl-octahydropyrano/hexahydrofuro[2,3-d]pyrimidin-2-one (thiones) and 5-aryl-substituted pyrano[2,3-d]pyrimidindione (2-thiones) derivatives through a one-pot multicomponent reaction using diversified hybrid catalysts such as organocatalysts, metal catalysts, ionic liquid catalysts, nanocatalysts, green solvents, catalyst-/solvent-free conditions, and miscellaneous catalysts as well as the mechanism and recyclability of the catalysts. This review mainly focuses on the application of hybrid catalysts (from 1992 to 2022) for the synthesis of 5H-pyrano[2,3-d]pyrimidine scaffolds. This review will definitely attract the world's leading researchers to utilize broader catalytic applications for the development of lead molecules.

Microwave-assisted multicomponent synthesis of antiproliferative 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones.

In this study, we demonstrate a simple, highly efficient, rapid and convenient series of 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones 4a-v. Microwave irradiation facilitates the one-pot multicomponent reaction of different aromatic aldehydes, 6-amino-2,4-dimethoxypyrimidine and dimedone using glacial acetic acid. Metal-free multicomponent synthesis, shorter reaction time, higher product yield, easy product purification without column chromatography and outstanding green credential parameters are the key features of this protocol. We analysed 4a-v against six human tumour cell lines for antiproliferative activity. 4h, 4o, 4q and 4v show good antiproliferative activity with a good in silico ADMET profile. Furthermore, 4h, 4o, 4q and 4v also show drug-likeness properties by obeying drug-like filters.

Versatile Synthetic Platform for 1,2,3-Triazole Chemistry.

1,2,3-Triazole scaffolds are not obtained in nature, but they are still intensely investigated by synthetic chemists in various fields due to their excellent properties and green synthetic routes. This review will provide a library of all synthetic routes used in the past 21 years to synthesize 1,2,3-triazoles and their derivatives using various metal catalysts (such as Cu, Ni, Ru, Ir, Rh, Pd, Au, Ag, Zn, and Sm), organocatalysts, metal-free as well as solvent- and catalyst-free neat syntheses, along with their mechanistic cycles, recyclability studies, solvent systems, and reaction condition effects on regioselectivity. Constant developments indicate that 1,2,3-triazoles will help lead to future organic synthesis and are useful for creating molecular libraries of various functionalized 1,2,3-triazoles.

One-pot two-step catalytic synthesis of 6-amino-2-pyridone-3,5-dicarbonitriles enabling anti-cancer bioactivity.

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.

Synthesis of N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles enabling PKBß/AKT2 inhibitory and in vitro anti-glioma activity.

A series of N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles was synthesised and screened for their potential to inhibit kinases and exhibit anticancer activity against primary patient-derived glioblastoma 2D cells and 3D neurospheres. A collection of 10 compounds was 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/PKBß. 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. Although exhibiting potency against glioma cells, 4j exhibited significantly less cytotoxicity against non-cancerous cells even at fourfold-fivefold the concentration. Herein we establish a novel biochemical kinase inhibitory function for N-(4-chlorophenyl) substituted pyrano[2,3-c]pyrazoles and further report their anti-glioma activity in vitro for the first time.KEY MESSAGEAnti-glioma pyrano[2,3-c]pyrazole 4j inhibited the 3D neurosphere formation in primary patient-derived glioma stem cells. 4j also displayed PKBß/AKT2 inhibitory activity. 4j is nontoxic towards non-cancerous cells.

Synthesis, crystal structure and in silico studies of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones.

Herein, acetic acid mediated multicomponent synthesis of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-one (2,4-dimethoxy-THPQs) was reported. Single-crystal XRD analysis of four newly developed crystals of 2,4-dimethoxy-THPQs and their DFT study were also reported. The structure of all molecules was optimized using DFT B3LYP/6-31G(d) level and compared with the corresponding single-crystal XRD data. As a result, the theoretical and experimental geometrical parameters (bond lengths and bond angles) were found to be in good agreement. Frontier molecular orbital (FMO) and molecule electrostatic potential (MEP) analyses were used to investigate the physicochemical properties and relative reactivity of 2,4-dimethoxy-THPQs. The formation of strong C-H⋯O and N-H⋯O interaction was investigated by Hirshfeld analysis. Furthermore, electronic charge density concentration in 2,4-dimethoxy-THPQs was analysed by the Mulliken atomic charges which helps to predict the ability of 2,4-dimethoxy-THPQs to bind in the receptor. The molecular docking of the crystal structure of 2,4-dimethoxy-THPQs in the main protease (Mpro) of SARS-CoV-2 suggested that all four 2,4-dimethoxy-THPQs efficiently docked in Mpro. Furthermore, 2,4-dimethoxy-THPQs with a 3-chloro substitution in the phenyl ring have the highest binding affinity because of the additional formation of halogen bonds and highest dipole moment.

Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degeneration in vivo.

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.

Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones.

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.

Pyridine-2-carboxylic acid as an effectual catalyst for rapid multi-component synthesis of pyrazolo[3,4-b]quinolinones.

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.

Hydroxyl alkyl ammonium ionic liquid assisted green and one-pot regioselective access to functionalized pyrazolodihydropyridine core and their pharmacological evaluation.

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.

Impact of an aryl bulky group on a one-pot reaction of aldehyde with malononitrile and N-substituted 2-cyanoacetamide.

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.