Design, Synthesis, and Biological Evaluation of New Potential Unusual Modified Anticancer Immunomodulators for Possible Non-Teratogenic Quinazoline-Based Thalidomide Analogs.

Sixteen new thalidomide analogs were synthesized. The new candidates showed potent in vitro antiproliferative activities against three human cancer cell lines, namely hepatocellular carcinoma (HepG-2), prostate cancer (PC3), and breast cancer (MCF-7). It was found that compounds XII, XIIIa, XIIIb, XIIIc, XIIId, XIVa, XIVb, and XIVc showed IC50 values ranging from 2.03 to 13.39 µg/mL, exhibiting higher activities than thalidomide against all tested cancer cell lines. Compound XIIIa was the most potent candidate, with an IC50 of 2.03 ± 0.11, 2.51 ± 0.2, and 0.82 ± 0.02 µg/mL compared to 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 µg/mL for thalidomide against HepG-2, PC3, and MCF-7 cells, respectively. Furthermore, compound XIVc reduced the expression of NFκB P65 levels in HepG-2 cells from 278.1 pg/mL to 63.1 pg/mL compared to 110.5 pg/mL for thalidomide. Moreover, compound XIVc induced an eightfold increase in caspase-8 levels with a simultaneous decrease in TNF-α and VEGF levels in HepG-2 cells. Additionally, compound XIVc induced apoptosis and cell cycle arrest. Our results reveal that the new candidates are potential anticancer candidates, particularly XIIIa and XIVc. Consequently, they should be considered for further evaluation for the development of new anticancer drugs.

Design, Synthesis, and Anti-Proliferative Action of Purine/Pteridine-Based Derivatives as Dual Inhibitors of EGFR and BRAFV600E.

The investigation of novel EGFR and BRAFV600E dual inhibitors is intended to serve as targeted cancer treatment. Two sets of purine/pteridine-based derivatives were designed and synthesized as EGFR/BRAFV600E dual inhibitors. The majority of the compounds exhibited promising antiproliferative activity on the cancer cell lines tested. Compounds 5a, 5e, and 7e of purine-based and pteridine-based scaffolds were identified as the most potent hits in anti-proliferative screening, with GI50 values of 38 nM, 46 nM, and 44 nM, respectively. Compounds 5a, 5e, and 7e demonstrated promising EGFR inhibitory activity, with IC50 values of 87 nM, 98 nM, and 92 nM, respectively, when compared to erlotinib's IC50 value of 80 nM. According to the results of the BRAFV600E inhibitory assay, BRAFV600E may not be a viable target for this class of organic compounds. Finally, molecular docking studies were carried out at the EGFR and BRAFV600E active sites to suggest possible binding modes.

Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline-Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors.

A series of quinoline-uracil hybrids (10a-l) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds 10a-l demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound 10h displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound 10l emerged as the best congener considering both activity (IC50 = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure-activity relationship revealed that bulky substituents at uracil N-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity.

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein.

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a-e and isatin derivatives 1a-c to synthesize spiro-oxindoles 3a-d, 4a-e, and 5a-e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5'-pyrido[2,3-d:6,5-d']dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.

In vitro antimicrobial evaluation and in silico studies of coumarin derivatives tagged with pyrano-pyridine and pyrano-pyrimidine moieties as DNA gyrase inhibitors.

Several coumarin-containing substitute nitrogen heterocycles have recently received considerable importance due to their diverse pharmacological properties. One-pot and rapid synthesis of coumarin derivatives was achieved via reactions of acetyl-coumarin with p-chloro-benzaldehyde and malononitrile to provide compound 2-containing cyano-amine using conventional heating. Compound 2 was condensed with different carbon electrophiles triethyl orthoformate, phenyl isocyanate, carbon disulfide, benzoyl chloride, and acetyl chloride that afforded the corresponding chromene derivatives 3-17. All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of the synthesized compounds were tested for antimicrobial activity against S. Pneumoniae, S. Epidermidis, S. Aureus, and E. coli as Gram + ve Bacteria, K. Pneumoniae, S. Paratyphi as Gram -ve Bacteria, P. Italicum, A. Fumigatus representative for Fungi. The preliminary screening results showed that most of the compounds had moderate to high activity against all tested organisms. The most potent four compounds were subjected to further investigation against E. Coli DNA gyrase and topoisomerase IV inhibitory activity, and the results showed that all of these derivatives inhibit DNA gyrase and thus cell division. Also, in silico studies were done for the most active compounds which showed good results.

Synthesis and anticancer evaluation of some novel pyrimido[5,4-e][1,2,4]triazines and pyrazolo[3,4-d]pyrimidine using DMF-DMA as methylating and cyclizing agent.

BACKGROUND: Described a series of main target compounds pyrimido[5,4-e][1,2,4]triazines is obtained via condensation of 6-hydrazinyluracil with different aromatic aldehydes to give the hydrazones followed by nitrosation with HNO2 then intramolecular cyclization. On the other hand, pyrazolopyrimidines can be obtained by the reaction of hydrazones with dimethylformamide-dimethylacetal (DMF-DMA), DMF-DMA in the presence of DMF or by refluxing the hydrazinyluracil with DMF-DMA in the presence of DMF directly. The newly synthesized compounds are evaluated in vitro for their anticancer activity against human lung carcinoma (A549). RESULTS: A newly substituted compounds of benzaldehyde-pyrimidin-4-yl)hydrazones (5a-f), pyrimido[5,4-e][1,2,4]triazines 6a-e, arylethylidenehydrazinylpyrimidine 7a,b and pyrazolopyrimidines 9,11 are screened for cytotoxic activity against human lung carcinoma (A549) cell line. They exhibited a good yield. Compound 6b shows the highest effect with IC50 value 3.6 µM, followed by compounds 9, 5a, 8, 5e, 6e, 5b, 5f, 7a, 5c, 6c, 7b, 6a, 11, 5d and 6d. CONCLUSION: A simple and efficient route is used for the synthesis of pyrimido[5,4-e][1,2,4]triazines and pyrazolopyrimidines. The synthesized compounds are screened for antitumor activity.

One pot synthesis, antimicrobial and antioxidant activities of fused uracils: pyrimidodiazepines, lumazines, triazolouracil and xanthines.

BACKGROUND: Uracil derivatives have a great attraction because they play an important role in pharmacological activities. Pyrimidodiazepines, lumazines, triazolopyrimidines and xanthines have significant wide spectrum activities including anticancer, antiviral as well as antimicrobial activities. RESULTS: A newly synthesized compounds pyrimido[4,5-b][1, 4]diazepines 5a-e, 6a-d, lumazines 7a-d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared in a good yields. The antimicrobial and antioxidant activities of compounds 5a, 5b, 6a, 6d and 8 exhibited a wide range activity against the pathogenic tested microbes (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Saccharomyces cerevisiae). Compound 8 showed activity against the fungus Aspergillus niger. The highest antioxidant activity was noticed for compound 5a. CONCLUSIONS: A series of novel pyrimido[4,5-b][1, 4]diazepines 5a-e, 6a-d, lumazines 7a-d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared from 5,6-diamino-1-(2-chlorobenzyl)uracil 3 in good yields. Compounds 5a-e, 6a-d were prepared by sequential manipulation of 3 with α,ß-unsaturated ketones. Lumazines 7a-d were obtained from 3 by treatment with phenacyl bromides in the presence of TEA. Compound 8 was prepared by treatment of 3 with HNO2, while xanthines 9, 10 were obtained from 3 by consecutive acetylation then intramolecular cyclodehydration or heating with malononitrile under solvent-free condition. The antimicrobial and antioxidant activity of this series was evaluated in vitro and they showed either weak or moderate activities. Graphical abstract Several pyrimido[4,5-b][1,4]diazepines, lumazines, triazolo-, and imidazolopyrimidines were synthesized from the starting compound 4,5-diaminouracils. The newly synthesized compounds were screened for both antimicrobial and antioxidant activities.