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In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). 8- N -Methyl- N -{[1-(7-chloroquinolin-4-yl)-1 H -1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment.

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC 50 values for 7a were 2.15 and 0.91 μM, and, for 7b, they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b , were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and K DEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a , b form stable complexes and the plateau phase started after 7 ns.

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3 - 5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid-spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3- O -(3',3'-dimethylsuccinyl)betulin (compound 3 ), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC 50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat ( BVM ) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4, 5, 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPARγ). According to the results of the docking, the best fit to the binding pocket of PPARγ was shown by compound 4., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this study, a series of regioisomeric acetylenic sulfamoylquinolines are designed, synthesized, and tested in vitro for their antiproliferative activity against three human breast cacer cell lines (T47D, MCF-7, and MDA-MB-231) and a human normal fibroblast (HFF-1) by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H -5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay. The antiproliferative activity of the tested acetylenic quinolinesulfonamides is comparable to that of cisplatin. The bioassay results demonstrate that most of the tested compounds show potent antitumor activities, and that some compounds exhibit better effects than the positive control cisplatin against various cancer cell lines. Among these compounds, 4-(3-propynylthio)-7-[ N -methyl- N -(3-propynyl)sulfamoyl]quinoline shows significant antiprolierative activity against T47D cells with IC 50 values of 0.07 µM. In addition, 2-(3-Propynylthio)-6-[ N -methyl- N -(3-propynyl)sulfa-moyl]quinoline and 2-(3-propynylseleno)-6-[ N -methyl- N -(3-propynyl)sulfamoyl]quinoline display highly effective atitumor activity against MDA-MB-231 cells, with IC 50 values of 0.09 and 0.50 µM, respectively. Furthermore, most of the tested compounds show a weak cytotoxic effect against the normal HFF-1 cell line. Additionally, in order to suggest a mechanism of action for their activity, all compounds are docked into the binding site of two human cytochrome P450 (CYP) isoenzymes. These data indicate that some of the title compounds display significant cytotoxic activity, possibly targeting the CYPs pathways.