Discovery of new pyrimido[5,4-c]quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies.

A novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5 have been synthesized, in good to excellent yields, via rapid base-catalyzed cyclization reaction of 2,4-dichloroquinoline-3-carbonitrile (5) with guanidine hydrochlorides 6a-c. All the synthesized compounds were screened for their in vitro antiproliferative activity. The most active hybrids 26a-d, 28a-d, and 30B were assessed against topoisomerase (topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I inhibitory activity while had weak topo IIα inhibitory action with compounds 30B and 28d, showed better topo I inhibitory activity than the reference camptothecin. Compound 30B, the most potent derivative as antiproliferative agent, exhibited moderate activity against CDK2 (IC50 = 1.60 µM). The results of this assay show that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these compounds is due to a different mechanism. Compounds 30B, 28d, and 28c were found to be the most potent against EGFR and their EGFR inhibitory activities (IC50 = 0.40 ± 0.2, 0.49 ± 0.2, and 0.64 ± 0.3, respectively) relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 µM). These results revealed that topo I and EGFR are attractive targets for this class of chemical compounds.

Advancements in the synthesis of fused tetracyclic quinoline derivatives.

Fused tetracyclic systems containing a quinoline nucleus represent an important class of heterocyclic bioactive natural products and pharmaceuticals because of their significant and wide-spectrum biological properties. Several of these compounds have been obtained with diverse pharmacological and biological activities, such as antiplasmodial, antifungal, antibacterial, potent antiparasitic, antiproliferative, anti-tumor and anti-inflammatory activities. This information will be beneficial for medicinal chemists in the field of drug discovery to design and synthesize new fused tetracyclic quinolines as potent therapeutical agents. This review article provides a comprehensive report regarding the methods developed for the synthesis of fused tetracyclic quinolines reported so far (till October 2019). The article includes synthesis by one-pot domino reaction, microwave synthesis using a catalyst, using ionic liquids, photocatalytic synthesis (UV radiation), Pfitzinger reaction, I2-catalyzed cyclization reaction, Wittig reaction, cascade reaction, imino Diels-Alder reaction, Friedel-Crafts reaction, CDC reaction, solvent-free reactions and using small chiral organic molecules as catalysts. To the best of our knowledge, this is the first review focused on the synthesis of fused tetracyclic quinolines along with mechanistic aspects.

Naphthyridines part 4: unprecedented synthesis of polyfunctionally substituted benzo[c][2,7]naphthyridines and benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridines with structural analogy to pyrido[4,3,2-mn]acridines present in the marine tetracyclic pyridoacridine alkaloids.

An easy, efficient and one-step synthesis of the versatile, hitherto unreported of polyfunctionally substituted benzo[c][2,7]naphthyridines 4a-c is described. The reaction of 4a-c with sodium azide gives the corresponding tetracyclic ring system 6a-c in near quantitative yield, and with phenyl isothiocyanate it gives the corresponding novel 3-alkyl-2-oxo-6-phenyl-5-thioxo-3,4,5,6-tetrahydro-2H-benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 8a-c. Refluxing compound 4a, with alkyl amines 9a-d for 2-3 h furnished 3-alkyl-5-alkylamino-4-amino-2-oxo-2,3-dihydrobenzo[c][2,7]naphthyridine-1-carbonitriles 10a-d, as stable crystalline solids. Compounds 10a-d reacted with acetic anhydride and triethyl orthoformate to furnish novel 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c]-pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 13a-c and 14a-c, respectively. Lastly, diazotization of 10a-c afforded the novel tetracyclic ring system 3,6-dialkyl-2-oxo-3,6-dihydro-2H-benzo[c][1,2,3]triazino[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 16a-c.

Synthesis and Characterization of New 1,2,4-Triazolo[1,5-a]pyridines That Extend the Life Span of Caenorhabiditis elegans via Their Anti-Inflammatory/Antioxidant Effects.

In the present study, we describe the synthesis of a new set of 1,2,4-triazolo[1,5-a]pyridines and their fused ring systems. The products were assayed for various types of biological activities like anti-inflammatory and antioxidative activity. Compounds 4c, 4f, 12a, 14, 16, and 19 were found to reduce carrageenan- and dextran-induced inflammation in rats. In addition, compounds 4f and 12a were found to have antioxidative radical scavenging activity. Furthermore, these compounds were tested in the model system Caenorhabiditis elegans and there increased heat stress resistance, reduced the formation of advanced glycation end products, and finally extended the life span.

Green chemistry: a facile synthesis of polyfunctionally substituted thieno[3,4-c]pyridinones and thieno[3,4-d]pyridazinones under neat reaction conditions.

A facile, solvent free, ecofriendly approach for the synthesis of pyridine-2,6-diones 4a-d, pyridazinone derivatives 8a-c and thienoazines 6 and 9 is herein described employing neat reaction conditions under both microwave and ultrasound irradiations. This solventless methodology is environmentally benign as it completely eliminates the use of solvent from the reaction procedure.

First synthesis and isolation of the E- and Z-isomers of some new Schiff bases. Reactions of 6-azido-5-formyl-2-pyridone with aromatic amines.

Some novel Schiff bases have been prepared by reacting 6-azido-5-formyl-2-pyridone 1 with a series of aromatic amines 2a-f. 5-Arylaminomethylene-6-(E)-aryl-iminopyridones 3a-e were obtained by reaction of 1 with 2a-e at room temperature, whereas with 2f, the 6-azido-5-naphthalen-2-yl-iminomethylpyridone derivative 4 was formed. On the other hand, heating 1 with 2a-d at 140-150 degrees C yielded two sets of isomeric products, (E)-3a-d and (Z)-5a-d. Refluxing compounds (Z)-3a,c with hydroxyl-amine in methanol gave the corresponding hydroxyliminopyridones 8a,c. Heating of (E)-3a-d with excess POCl3 at reflux did not give the expected tricyclic compound 9, but rather the isomeric products (Z)-5a-d were obtained. The structures of all these products have been characterized using IR and 1H- and 13C-NMR spectroscopy.