New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a–d demonstrated significant antioxidant activity, while 7c,d, 8c,d, and 9c,d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b, 3a,b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

The title compounds were prepared by reaction of 6-acetyltetralin (1) with different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflouro-benzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding a,b-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b, 2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared compounds were evaluated for anticancer activity against two human tumor cell lines. Compound 3a showed the highest potency with IC₅₀ = 3.5 and 4.5 μg/mL against a cervix carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.

The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a–e, 6, 7, 8a–c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a–g. The compounds 5a–e, 6, 7, 8a–c, 9, 10a, 10b, 14a, 14b and 15a–g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds—4f, 4i, 4a, 4g, and 4d—possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC₅₀ values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC₅₀ value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein–ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski’s rule of five and Veber’s rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

In this work, novel imadazo[1,2-a]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2-a]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC₅₀ of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC₅₀s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2-a]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC₅₀ of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.