Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021-Present).

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021-2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.

Discovery of novel benzofuran-based derivatives as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis, biological evaluation, molecular docking and 3D-QSAR investigation.

A series of novel benzofuran-based compounds 7a-s were designed, synthesized, and investigated in vitro as acetylcholinesterase inhibitors (AChEIs). Compounds 7c and 7e displayed promising inhibitory activity with IC50 values of 0.058 and 0.086 µM in comparison to donepezil with an IC50 value of 0.049 µM. The new molecules' antioxidant evaluation revealed that 7c, 7e, 7j, 7n, and 7q produced the strongest DPPH scavenging activity when compared to vitamin C. As it was the most promising AChEI, compound 7c was selected for further biological evaluation. Acute and chronic toxicity studies exhibited that 7c showed no signs of toxicity or adverse events, no significant differences in the blood profile, and an insignificant difference in hepatic enzymes, glucose, urea, creatinine, and albumin levels in the experimental rat group. Furthermore, 7c did not produce histopathological damage to normal liver, kidney, heart, and brain tissues, ameliorated tissue malonaldehyde (MDA) and glutathione (GSH) levels and reduced the expression levels of the APP and Tau genes in AD rats. Molecular docking results of compounds 7c and 7e showed good binding modes in the active site of the acetylcholinesterase enzyme, which are similar to the native ligand donepezil. 3D-QSAR analysis revealed the importance of the alkyl group in positions 2 and 3 of the phenyl moiety for the activity. Overall, these findings suggested that compound 7c could be deemed a promising candidate for the management of Alzheimer's disease.

Novel substituted 1,8-naphthyridines: Design, synthesis, radiolabeling, and evaluation of apoptosis and topoisomerase II inhibition.

A series of seventeen 1,8-naphthyridine derivatives (5a-5q) conjugated at N1 to various substituted phenyl rings were designed and synthesized as potential topoisomerase II (Topo II) inhibitors. The antiproliferative activity of the target compounds against three cancer cell lines showed that compounds 5g and 5p had the highest antiproliferative activity. In addition, 5p and 5g displayed a high selectivity index (SI) for cancer cells when tested on WI38 normal cells, whereby compound 5p showed the highest SI. Furthermore, 5g and 5p induced cell cycle arrest at the S and G1/S phases, respectively, triggering apoptosis in HepG-2 cells. The in vitro Topo II inhibitory effect (plasmid-based) of both compounds revealed that 5p had better inhibition of Topo II. In addition, 5p displayed potent topoisomerase IIß inhibitory effect when compared to known topoisomerase inhibitors (doxorubicin and topotecan). Molecular docking proposed a unique binding pattern of 5p in the etoposide binding pocket of topoisomerase IIß, endorsing its potential role as a Topo II poison. Accordingly, 5p was chosen for radioiodination to study the degree of tumor localization following administration in solid tumor-bearing mice. The radioiodinated 5p showed a selective localization at the tumor site, which further confirmed the value of 5p as a lead 1,8-naphthyridine anticancer agent.

Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases.

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC50 values (0.002 - 0.004 µM) comparing to Staurosporine of IC50; 0.005 µM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC50 range 0.0149 - 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-ß, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-ß of IC50 values 0.17 × 10-3, 0.07 × 10-3 µM in comparison with the reference drug sorafenib of IC50; 0.28 × 10-3, 0.13 × 10-3 µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.

C-CN bond formation: an overview of diverse strategies.

Nitrile or cyano compounds are an important part of structural motifs in dyes, agrochemicals, medicinal compounds, and electronic materials. Also, aryl nitrile is an important intermediate in the preparation of numerous compounds via transformations such as hydrolysis, hydration, reduction, cycloadditions, and nucleophilic additions. Such methods are beneficial for introducing sensitive functional groups in various positions in the multi-step synthesis of natural products and medicinal compounds. In the past decades, various cyanation methods have been reported in the vast arena of chemistry, which have made several building blocks accessible. Previously reported cyanation reviews, letters, and perspectives are written in parts. Thus, today a comprehensive review that will be able to guide readers through the vast pool of C-CN bond forming reactions via different approaches is obligatory. The present feature article depicts the various areas of cyanation methodologies that are based on the metal catalyst used, directed, non-directed, electrochemical, photochemical, asymmetric, and radical based approaches. This feature article will serve as a comprehensive tool to navigate the C-CN (cyanation) reactions across the vast area in synthetic chemistry.

Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors.

Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.

Highly Efficient Nanosized Mesoporous CuMgAl Ternary Oxide Catalyst for Nitro-Alcohol Synthesis: Ultrasound-Assisted Sustainable Green Perspective for the Henry Reaction.

Nanosized mesoporous CuMgAl ternary oxide catalysts were prepared by thermal decomposition of CuMgAl-layered double hydroxides at 500 °C with nominal Cu/Mg/Al ratios of 1:1:1 (Cu-LDH-I), 1.5:0.5:1 (Cu-LDH-II), and 2:0:1 (Cu-LDH-III). The synthesized catalysts were characterized by inductively coupled plasma atomic emission spectroscopy (ICP-AES), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), Fourier transform infrared (FTIR) spectroscopy, CO2-TPD, and N2 physisorption analysis techniques. The catalytic activity of the synthesized materials was investigated for the Henry reaction between nitromethane and numerous aldehyde derivatives under ultrasonic irradiation. The three CuMgAl ternary oxide catalysts exhibited a high catalytic activity, forming nitro alcohol products with 100% atom economy. The CuMgAl-I catalyst derived from Cu-LDH-I offered high turnover frequencies (TOFs in the synthesis of all of the nitro alcohols in shorter reaction times). The superior catalytic activity of the CuMgAl-I sample is attributed to the synergistic effect between the physicochemical properties of the catalysts and ultrasonic irradiation. The HRTEM analysis of the used CuMgAl-I catalyst revealed the evidence for the cavitation collapse, which causes localized deformation and surface erosion. Moreover, the synthesized catalysts also exhibited robust sustainable activity that resisted deactivation over repeated usage. The present example of ultrasonic-assisted catalyzed organic synthesis represents a novel strategy for the solvent-free green synthesis of nitro-alcohols by the Henry reaction with 100% atom economy.

Synthesis and Characterization of New Dihydronaphthalene Candidates as Potent Cytotoxic Agents against MCF-7 Human Cancer Cells.

In the present work, a new series of dihydronaphthalene derivatives were synthesized starting with 6-methoxy-1-tetralone 1, and the corresponding hydrazine derivative 2. Reaction of compound 2 with aryl isothiocyanates produced thiosemicarbazides 3a-d, which were reacted with ethyl chloroacetate to give thiazolidinone derivatives 4a-d. Pyrano thiazolecarbonitrile derivatives 5a-f were prepared by heating a mixture of compounds 4a or 4c, aryl aldehydes, and malononitrile utilizing distilled water in the presence of catalytic amount of potassium hydrogen phthalate. Also, treatment of 4a with DMF-DMA under solvent-free conditions gave enaminone derivative 6, which condensed with ethyl acetoacetate or acetylacetone or malononitrile or cyanothioacetamide to give compounds 7-10, respectively. Finally, reaction of the enaminone 6 with 2-aminoimidazol or 2-aminothiazol in the presence of glacial acetic acid produced derivatives 11 and 12, respectively. Cytotoxic evaluation of eleven compounds, against MCF-7 (human breast adenocarcinoma) cell lines, was estimated. Results revealed that five of the examined compounds 5a, 5d, 5e, 10, and 3d showed potent cytotoxic activities recording, IC50 values; 0.93 ± 0.02, 1.76 ± 0.04, 2.36 ± 0.06, 2.83 ± 0.07, and 3.73 ± 0.09 µM, respectively, which were more potent than the reference used (Saturosporin, IC506.08 ± 0.15 µM). The new products were also examined towards normal epithelial breast cells (MCF10A). All of them showed very good safety profile with different degrees and were safer than the reference drug used. Compound 5a was the most effective against MCF-7 cells and was less toxic than Saturosporin by about 18.45-folds towards MCF01A normal cells. All the new compounds were fully characterized by the different spectral and analytical tools. Herein, detailed syntheses, spectroscopic, and biological data are reported.

Synthesis, biological screening, and molecular docking of quinazolinone and quinazolinethione as phosphodiesterase 7 inhibitors.

N-Substituted isatoic anhydrides were used as starting materials for the synthesis of compounds 5-16 through alkali hydrolysis, Schiff base reactions, and oxidation. Compounds 18-23 were obtained by thionation of their oxo isosteres using Lawesson's reagent. Cyclocondesation of anthranilic acid with thiourea afforded compounds 25-27, which were S-alkylated to afford compounds 28-30, which were thionated using Lawesson's reagent to afford 31-33. The compounds were tested for their in vitro inhibitory activity against the phosphodiesterase 7A (PDE7A) enzyme compared with the selective PDE7 inhibitor BRL50481. All the compounds showed the inhibitory activity on the enzyme at micromolar levels. Compounds 9 and 25 showed the highest inhibitory activity on the enzyme: IC50 = 0.096 and 0.074 µM, respectively, comparable to BRL50481 (IC50 = 0.072 µM). The binding mode and binding affinity of the target compounds at the enzyme PDE7A-binding site were studied through molecular docking. Compounds 9 and 25 showed good recognition at the enzyme-binding site and were capable of binding in an inhibitory mode similar to the reference compound BRL50481, forming the necessary interactions with the key amino acids. Docking studies and enzyme assay were in agreement.

Nanostructured Mg-Al hydrotalcite as catalyst for fine chemical synthesis.

This paper reviews the recent research of nanostructured Mg-Al hydrotalcite (Mg-Al HT) and its application as an efficient solid base catalyst for the synthesis of fine chemicals. Mg-Al HT has many beneficial features, such as low cost, selectivity, catalytic properties, and wide range of preparation and modification methods. They hold promise for providing sought-after, environmentally friendly technologies for the 21st century. Replacement of currently used homogeneous alkaline bases for the synthesis of fine chemicals by a solid catalyst can result in catalyst re-use and waste stream reduction. We introduce briefly the structure, properties and characterization of the nanostructured Mg-Al HT. The efficacy and benign applications of Mg-Al HT as an alternative solid base to homogenous catalysts in the synthesis of fine chemicals are then reviewed. The challenges for the future applications of Mg-Al HT in the synthesis of fine chemicals in terms of green protocol processes are discussed.