Synthesis, Antimicrobial Evaluation, DFT, and Molecular Docking Studies of Pyrano [4,3-b] Pyranone and Pyrano[2,3-b]Pyridinone Systems.

Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic system 6 and spiro hybrid molecule 7. Also, the reaction of DHA 1 with cyanoacetamide derivatives 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworks 9 and 12, respectively. Also, in silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively.

Pyrimido[5,4-c]quinolines: Synthesis from 3,4-Di-functionallized Quinoline, Reactivity and Biological Activities.

Quinoline and pyrimidine moieties are ubiquitous components in both natural and synthetic compounds, showcasing diverse applications. The fusion of these well-known structures into hybrid molecules has garnered attention due to their intriguing biological properties. Particularly in the field of medicinal chemistry, numerous studies in the last decade have focused on pyrimido[5,4-c]quinoline ring systems (PyQs5,4-c). This review elucidates the synthesis of PyQs5,4-c and their derivatives using 3,4-difunctionalized quinoline as a key starting material. The preparation of PyQs5,4-c involves a series of chemical transformations, including the Friedländer, Ullmann and Biginelli reaction, Vilsmeier-Haack formylation, Suzuki coupling, and a one-pot three-component reaction. These synthetic routes not only offer access to diverse PyQs5,4-c derivatives.

An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo- and Anil-Linked with 3-Aminopyrazolo[3,4-b]pyridine.

In this project, an effective procedure for constructing a new combination of pyrazolo[3,4-b]pyridine was depicted through the coupling of diazonium salt 2 of heterocyclic amine 1 with active methylene, enamine, and amidine moieties such as 3, 5, 7, and 9 at 0-5 °C in pyridine to afford hydrazinylhydrazonoyl derivatives 4, and diazenylheterocyclic derivatives 6, 8, and 10, respectively. Also, aminopyrazolo[3,4-b]pyridine 1 condensed with different aryl or heteroaryl aldehydes in EtOH/AcOH gave the corresponding aldimine 14, 15, 16. Compound 15 was cyclized via refluxing in DMF for 6 h to afford 18, while the transformation of compound 16 with an alkyl halide afforded 19a, b. The synthesized compounds, explicated by spectral data and elemental analysis, were examined for their antitumor activities. The in vitro cytotoxic activity of new pyrazolo[3,4-b]pyridines against the A2780CP, MCF-7, and HepG-2 cell lines was evaluated using the reference doxorubicin. Compounds 15 and 19a exhibited high reactivity against the A2780CP cell lines, with IC50 values of 35 and 17.9 µM, respectively. Also, compound 28 had the cytotoxic potential for A2780CP and MCF-7 cell lines, with IC50 values of 14.5, and 27.8 µM, respectively.

Synthesis of new thienylnicotinamidines: Proapoptotic profile and cell cycle arrest of HepG2 cells.

Fourteen new thienylnicotinamidines and their analogs 5a-5k, 12, 13a, and 13b were prepared and their antiproliferative potential was evaluated against the growth of 60 cancer cell lines. The tested compounds had a strong antiproliferative efficacy against almost all cancer cell lines, with the average GI50 at ~2.20 µM. The effect of the thienylnicotinamidines on the growth of normal lung fibroblast cells (WI-38) indicated that these derivatives are safe to the normal cells. The selectivity index (SI) ranges from 5.5- to 42.0-fold. The conceivable mechanisms of action of the effective compounds 5d, 5f, 5g, 5i, 5j, and 5k with high SI were investigated. Although the thienylnicotinamidines are similar in structure, they could be divided into three groups as per their effects on gene expression: The first group (5d and 5f) elevated p53 and caspase 3 expression, the second group (5g and 5i) elevated p53 expression, and the last group (5j and 5k) elevated p53 and reduced topoII expression. Many thienylnicotinamides inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) in cell lysates at concentrations comparable to or better than pazopanib. The data of caspase 3 expression were confirmed by measuring the protein level by Western blot and the activity of the cleaved active enzyme. The ability to arrest the cell cycle and induce apoptosis was confirmed by flow cytometry. Taken together, two derivatives, 5d and 5f, with a distinctive VEGFR-2 inhibitory activity and a proapoptotic and cell cycle arrest profile merit further investigations.

Synthesis of new thienylpicolinamidine derivatives and possible mechanisms of antiproliferative activity.

Three thienylpicolinamidine derivatives 4a-c were prepared from their corresponding picolinonitriles 3a-c on treatment with lithium trimethylsilylamide, LiN(TMS)2, followed by a de-protection step using ethanol/HCl (gas). DFT calculations were used to optimize the geometric structure of the newly synthesized picolinamidines. The comparison of DFT calculated spectral data with the experimental data (1H-NMR and 13C-NMR) showed a good agreement. The in vitro antiproliferative activity of the cationic compounds 4a-c was determined against 60 cancer cell lines representing nine types of cancer. The tested picolinamidines were highly active with compounds 4a and 4b eliciting mainly cytotoxic activity with GI values ranging from -7.17 to -86.03. Leukemia (SR and K-562), colon (SW-620 and HT29), and non-small cell lung cancer (NCI-H460) cell lines were the most responsive to the investigated picolinamidines. In particular, 4-methoxyphenyl derivative 4a showed a profound growth deterring power with GI50 of 0.34 µM against SR, 0.43 µM against SW-620, and 0.52 µM against NCI-H460. The three tested picolinamidines elicited potent GI50 values against all tested cell lines at low micromolar to sub-micromolar level. The new picolinamidines were selective and did not affect normal human fibroblasts. The selectivity index ranged from 13-21 µM. The novel picolinamidines downregulated the expression of key genes in the cell cycle, cdk1 and topoII, but did not affect p53 or txnrd1. Compounds 4b and 4c caused a significant reduction in the concentrations of TopoII and MAPK proteins but were devoid of any effect on the activity of caspase 3. Taken together, these promising anticancer candidates are effective at very low concentrations and safe to normal cells, and most probably work through arresting the cell cycle, and therefore, they deserve further investigations.

Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs.

This review highlights the recently cited research data in the literature on the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs and their applications over the period from 2013 to 2017. It covers: synthesis of quinoline ring systems and reactions adopted to construct fused or binary quinoline-cord heterocyclic systems. The biological evaluation and the synthetic applications of the target compounds were illustrated.

Synthesis, characterization and RHF/ab initio simulations of 2-amino-1,3,4-thiadiazole and its annulated ring junction pyrimidine derivatives.

Michael addition reaction of the 2-amino-1,3,4-thiadiazole to chalcone as biselectrophile afforded 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3) instead of 5,7-diphenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine (5) via further Michael addition at C5 in pyrimidine moiety. The structure 3 was established through the aspect of ab initio calculations, elemental analysis and spectral data.

Facile construction of substituted pyrimido[4,5-d]pyrimidones by transformation of enaminouracil.

The reaction of 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1) as a binucleophile with primary aromatic or heterocyclic amines and formaldehyde or aromatic (heterocyclic) aldehydes in a molar ratio (1:1:2) gave the pyrimido[4,5-d]pyrimidin-2,4-dione ring systems 2-5. Treatment of 1 with diamines and formalin in molar ratio (2:1:4) gave the bis-pyrimido[4,5-d]pyrimidin-2,4-diones 6-8. Furthermore, substituted pyrimido[4,5-d]pyrimidin-2,4-diones with uracil derivative 11 or spiro indole 16 were synthesized. Synthesis of pyrimido[4,5-d]pyrimidin-2,4-diones with different substitution at C-5 and C-7 was achieved to give 13 and 18, respectively.

Efficient regioselective synthesis and potential antitumor evaluation of isoxazolo[5,4-b]pyridines and related annulated compounds.

The reaction of 5-amino-3-methylisoxazole with appropriate α,ß-unsaturated ketones gave the corresponding isoxazolo[5,4-b]pyridines. Treatment of 1 with 2,6-dibenzylidenecyclohexanone or 2-benzylidenedimedone afforded the corresponding isoxazolo[5,4-b]quinoline derivatives. 4,6,8,9-Tetrahydroisoxazolo[5,4-b]quinolin-5-one derivative was also obtained by multicomponent condensation reaction of 1 with dimedone and benzaldehyde. Heterocyclic annulation of the isoxazolo[5,4-b]pyridine system was achieved via reaction of 1 with benzylidene derivatives of indandione, quinuclidone, pyrazolone, and oxazolone. A representative of some newly synthesized compounds was evaluated as antitumor agents.

Synthesis and antioxidant evaluation of some new 3-substituted coumarins.

3-Acetylcoumarin (1) was utilized as a key intermediate for the synthesis of 2-aminothiazole derivative 3 via bromination of 1 to afford acetylbromide 2 followed by treatment with thiourea or via Biginelli reaction of 1. Treatment of 3 with 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-methyl-4H-benzo[d][1,3]oxazin-4-one, furo[3,4-b]pyrazine-5,7-dione or 2-methyl-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d][1,3]oxazin-4-one afforded diazine derivatives 4-7. Also, pyridopyrimidine 8 was obtained via a one pot reaction of 6-aminothiouracil, p-chlorobenzaldehyde and 3-acetylcoumarin. Moreover, refluxing of 6-aminothiouracil with one equivalent amount of 2 afforded the thiazolopyrimidine 9, while the pyrrolothiazolopyrimidine 10 was revealed when two equivalent amounts of 2 was used. Furthermore, treatment of enamine 11 with 2-aminobenzothiazole or 6-aminothiouracil afforded the pyrimidine derivatives 12 and 13, respectively. Transamination of enamine 11 with m-anisidine followed by cyclization of the resulting enaminone 14 gave the desired quinoline 15. Also, treatment of 11 with thiophenol in dioxane gave the mercapto derivative 16. Moreover, coupling of 11 with 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-yl-diazonium chloride, followed by complete cyclization of the resulting product afforded the pyridopyrazolothiazine 19 via the intermediate 18. Furthermore, the pyrazolopyrimidine 20 was revealed via a one pot condensation of 11, 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and ammonium acetate. The thiadiazine derivatives 21-23 were obtained via treatment of 2 with the corresponding o-aminothiols. Desulphonation of 23 afforded the pyrazolotriazine 24. Finally, reaction of 2 with 2-hydroxybenzaldehyde gave benzofuran derivative 25. Representative compounds of the synthesized products were evaluated as antioxidant agents.