Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies.

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection's spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds' physical and chemical features, including molecular dynamic (MD) simulations, protein-ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral Mpro protein and may have emerged as a novel COVID-19 curative option.

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity.

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

Discovery of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as novel CDK2 inhibitors: synthesis, biological and molecular modeling investigations.

CDK2 inhibition is an appealing target for cancer treatment that targets tumor cells in a selective manner. A new set of small molecules featuring the privileged pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4-13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds. The growth of the three examined cell lines was significantly inhibited by most of the prepared compounds. Results revealed that most of the compounds showed superior cytotoxic activities against MCF-7 and HCT-116 with IC50 range (45-97 nM) and (6-99 nM), respectively, and moderate activity against HepG-2 with IC50 range of (48-90 nM) compared to sorafenib (IC50: 144, 176 and 19 nM, respectively). Of these compounds, 14 & 15 showed the best cytotoxic activities against the three cell lines with IC50 values of 45, 6, and 48 nM and 46, 7, and 48 nM against MCF-7, HCT-116 and HepG-2, respectively. Enzymatic inhibitory activity against CDK2/cyclin A2 was achieved for the most potent anti-proliferative compounds. Compounds 14, 13 and 15 revealed the most significant inhibitory activity with IC50 values of 0.057 ± 0.003, 0.081 ± 0.004 and 0.119 ± 0.007 µM, respectively compared to sorafenib (0.184 ± 0.01 µM). Compound 14 displayed potent dual activity against the examined cell lines and CDK2, and was thus selected for further investigations. It exerted a significance alteration in cell cycle progression, in addition to apoptosis induction within HCT cells. Molecular docking simulation of the designed compounds confirmed the good fit into the CDK2 active site through the essential hydrogen bonding with Leu83. In silico ADMET studies and drug-likeness studies using a Boiled Egg chart showed suitable pharmacokinetic properties which helped in structure requirement prediction for the observed antitumor activity.

Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives.

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.

Synthesis and anti-hepatitis B activity of new substituted uracil and thiouracil glycosides.

A number of N- and S-substituted uracil and thiouracil glycosides were synthesized by coupling reaction of 5,6-dibenzyle pyrimidine derivatives with the corresponding acetobromosugar. The synthesized compounds were tested for their antiviral activity against hepatitis B virus. Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds which showed moderate to high antiviral activities.

Synthesis and antiviral evaluation of novel 5-(N-Aryl-aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and their sugars, 1,2,4-triazoles, tetrazoles and pyrazolyl derivatives.

A number of new N-arylaminomethyl-1,3,4-oxadiazole derivatives 2, 3a,b, and 9-12a,b were prepared. Sugar (5-N-arylaminomethyl-1,3,4-oxadiazol-2-yl) hydrazones 4-6a,b were synthesized by the reaction of the hydrazino derivatives 3a,b with the corresponding monosaccharides. The novel acyclo-C-nucleosides 7, 8a,b were prepared by heterocyclization of the sugar hydrazones 4, 5a,b with acetic anhydride. A number of the synthesized compounds were tested for their antiviral activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBBcell culture-adapted strain). The results revealed that the sugar hydrazones 6a,b showed higher antiviral activity compared to the other hydrazones and their acetylated derivatives.

Synthesis and antiviral evaluation of some sugar arylglycinoylhydrazones and their oxadiazoline derivatives.

Sugar N-arylaminoacetylhydrazones 2-5 were prepared by the reaction of N-arylaminoacetylhydrazides 1 with equivalent amounts of the corresponding monosaccharides. Per-O-acetyl derivatives 6-9 of sugar hydrazones 2-5 were prepared by using acetic anhydride in pyridine at room temperature, while on boiling with acetic anhydride, cyclization had taken place to give the oxadiazolines 10-12. The prepared compounds were tested for antiviral activity against Herpes Simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV, MBB-cell culture adapted strain). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds.