Discovery of a novel pyrido[1,2-a]thiazolo[5,4-d]pyrimidinone derivatives with excellent potency against acetylcholinesterase.

As mimetic compounds of the natural alkaloid mackinazolinone, forty pyrido[1,2-a]thiazolo[5,4-d] pyrimidinone were designed and synthesized from a bioisosterism approach. The structure of these compounds was confirmed through analysis using 1H NMR, 13C NMR, and HRMS techniques. All the compounds were evaluated for their anticholinesterase activities and cytotoxicity on normal cells (293 T) by the Ellman method and methyl thiazolyl tetrazolium (MTT) method in vitro. and the structure-activity relationships (SARs) were summarized. The results showed that most of the compounds effectively inhibited acetylcholinesterase (AChE) in the micromolar range with weak cytotoxicity. Compound 7o exhibited the best inhibitory activity against AChE, displaying an IC50 values of 1.67 ± 0.09 µM and an inhibitory constant Ki of 11.31 µM as a competitive inhibitor to AChE. Molecular docking indicated that compound 7o may bind to AChE via hydrogen bond and π-π stacking. Further molecular dynamics (MD) simulations indicated a relatively low binding free energy (- 27.91 kJ·mol-1) of compound 7o with AChE. In summary, the collective findings suggested that 7o was promising as a potential novel drug candidate worthy of further investigation for the treatment of Alzheimer's disease.

Discovery of novel (E)-1-methyl-9-(3-methylbenzylidene)-6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one as DDR2 kinase inhibitor: Synthesis, molecular docking, and anticancer properties.

We report the synthesis, molecular docking and anticancer properties of the novel compound (E)-1-methyl-9-(3-methylbenzylidene)-6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one (PP562). PP562 was screened against sixteen human cancer cell lines and exhibited excellent antiproliferative activity with IC50 values ranging from 0.016 to 5.667 µM. Experiments were carried out using the target PP562 at a single dose of 1.0 µM against a kinase panel comprising 100 different enzymes. A plausible binding mechanism for PP562 inhibition of DDR2 was determined using molecular dynamic analysis. The effect of PP562 on cell proliferation was also examined in cancer cell models with both high and low expression of the DDR2 gene; PP562 inhibition of high-expressing cells was more prominent than that for low expressing cells. PP562 also exhibits excellent anticancer potency toward the HGC-27 gastric cancer cell line. In addition, PP562 inhibits colony formation, cell migration, and adhesion, induces cell cycle arrest at the G2/M phase, and affects ROS generation and cell apoptosis. After DDR2 gene knockdown, the antitumor effects of PP562 on tumor cells were significantly impaired. These results suggested that PP562 might exert its inhibitory effect on HCG-27 proliferation through the DDR2 target.

Design, combinatorial synthesis and cytotoxic activity of 2-substituted furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library.

A facile protocol was developed for the combinatorial synthesis of furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library via a one-pot condensation, from 2-amino furans/pyrroles. Herein reported process required a similar reaction condition, providing mild access to two diverse series of natural product-like heterocycles. Both furo[2,3-d]pyrimidinones and pyrrolo[2,3-d]pyrimidinones were evaluated in vitro against a panel of human cancer cell lines including against human cancer HeLa (cervical), MCF-7 (breast) and HT-29 (colon) cell lines. Derivative 12n ((2-(4-chlorophenyl)-1-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrrolo[2,3-d]pyrimidin-4(1H)-one)) showed high activity (IC50 = 6.55 ± 0.31 µM) against the HeLa cell line. These products could be subjected to a various modification and therefore represent important skeletons for the anticancer drug discovery.

Furo[2,3-d]pyrimidines as Mackinazolinone/Isaindigotone Analogs: Synthesis, Modification, Antitumor Activity, and Molecular Docking Study.

The chemical transformation of the tricyclic furo[2,3-d]pyrimidines was performed under isosteric and scaffold-hopping strategies focusing on the synthesis of its arylidene and imine-containing derivatives. Naturally-occurring alkaloids mackinazolinone and isaindigotone were as templates of target heterocycles. Synthesized compounds evaluated for their antitumor activity on human cancer cervical HeLa, breast MCF-7, and colon HT-29 cell lines. Four compounds: 8c, 8e, 10b, and 10c demonstrated potency against HeLa and HT-29 cell lines, and IC50 values were between 7.37-13.72 µM, respectively. The molecular docking results showed that compounds 8c and 10b had good binding and high matching with the target EGFR protein.

Synthesis and anticancer activity of ethyl 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks.

A series of 5-amino-1-N-substituted-imidazole-4-carboxylate building blocks was synthesized and assayed for their antiproliferative potential against human cancer cell lines, including HeLa (cervical), HT-29, HCT-15 (colon), A549 (lung), and MDA-MB-231 (breast) cells. The preliminary screening results revealed that several derivatives containing alkyl chains at the N-1 position of the imidazole core demonstrate a certain inhibitory effect on growth and proliferation. A significant effect was observed following ethyl 5-amino-1-dodecyl-1H-imidazole-4-carboxylate (5e) treatment for 72 h. The IC50 value for HeLa cells was 0.737 ± 0.05 µM, whereas that for HT-29 cells was 1.194 ± 0.02 µM. Further investigations revealed that 5e significantly inhibited tumor cell colony formation and migration, and it exhibited antiadhesive effects on HeLa cells as well as antitubulin activity along with the induction of early apoptosis of HeLa and HT-29 cells. In addition, derivative 5e significantly reduced the cell mitochondrial membrane potential in a dose-dependent manner and induced early apoptosis of HeLa and HT-29 cells, indicating that 5e may serve as a lead compound for further drug discovery and development.

Straightforward synthesis, characterization, and cytotoxicity evaluation of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones.

Dozens of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones were synthesized in a straightforward method by condensation of substituted 2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-diones or N-methyl-2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-dione with 3,4-dihydro-ß-carbolines. In vitro cytotoxic assay discovered that compounds 9a, 10e, 11a, 11d, 11f, and 12a could induce antiproliferation against four different types of human cancer cells while compounds 10f and 12e were inactive. Notably, compound 11a displayed potent cell cytotoxicity for human non-small cell lung cancer cells A549, PC-9, human prostate cancer cells PC-3, and human breast cancer cell line MCF-7. Furthermore, compound 11a exhibited strong colony formation inhibition to A549 cells. These results unfold potential anticancer therapeutic applications of hybrids of thieno[2,3-d]pyrimidinones and quinazolinones.

Structure-activity relationship studies of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters against influenza viruses.

A series of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters were synthesized via the condensation of methyl rupestonate with various aldehydes in the presence of LDA. This mixed aldol reaction was highly stereoselective and all the new compounds were elucidated by detailed NMR and MS analyses. The absolute configurations of the newly formed stereocenters were further confirmed by X-ray crystallographic analysis of 3d, the results of which were found to be opposite to the prediction based on Zimmerman-Traxler's and Houk's models. All the compounds synthesized were then evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and B viruses. The data showed that 3p displayed the highest activity against influenza A H1N1 (IC50=0.69µg/mL) and H3N2 (IC50=0.69µg/mL) viruses, which were even better than Ribavirin and Oseltmivir. On the other hand, both 3c and 3o were found to show comparable activities with the reference drugs in inhibiting both influenza A and B viruses. Further studies will focus on reducing the cytotoxicity of the hits reported in this work.

Novel pyrazolo[3,4-d]pyrimidines as potential anticancer agents: Synthesis, VEGFR-2 inhibition, and mechanisms of action.

Novel pyrazolo[3,4-d] pyrimidine derivatives bearing carbon-aryl(heteryl)idene moieties were synthesized via a condensation reaction of 5-aminopyrazoles and cyclic lactams. The preparation of the target compounds employed bioisosterism, where a pyrazole ring was a major replacement. Fifteen target compounds were investigated for their antiproliferative activity on five human cancer cell lines; derivative (E)- 1-methyl-9-(3,4,5-trimethoxybenzylidene)- 6,7,8,9-tetrahydropyrazolo[3,4-d]pyrido[1,2-a]pyrimidin-4(1H)-one (10k) showed the highest activity (IC50 value (0.03-1.6 µM), on selected cell lines. Results of an in vivo experiment on an HT-29 xenograft nude mouse model also confirmed that 10k inhibited tumor growth. The proposed anticancer mechanism of 10k in HT-29 and HCT-116 cells was that 10k caused G2/M phase arrest in cancer cells and decreased the mitochondrial membrane potential (Δψmt). Additional studies were conducted on HUVEC, where 10k significantly inhibited HUVEC cell migration, adhesion, and tube formation activity. Molecular modeling studies revealed that 10k forms hydrogen bonds with cys-919 of vascular endothelial growth factor receptor 2 (VEGFR-2) and inhibit VEGFR-2 kinase activity. Moreover, tubulin polymerization assay results showed that 10k formed hydrogen bonds with Asn-101 and Gln-11 of tubulin. Furthermore, it could change the aberration of microtubule arrangements in HUVEC and inhibit tubulin polymerization. These results indicate that the main anticancer activity of 10k may be mediated by anti-vascular effects and inhibition of tubulin polymerization in pre-clinical trials.