Medicinal Chemistry Research

Correction to: Synthesis, molecular docking, and apoptogenic efficacy of novel N-heterocycle analogs to target B-cell lymphoma 2/X-linked inhibitors of apoptosis proteins to regress melanoma The original version of this article unfortunately contained an error in author group. The first author name was repeated twice.

Chemical constituents of the Vietnamese plants Dalbergia tonkinensis Prain and Cratoxylum formosum (Jack) Dyer in Hook and their DPPH radical scavenging activities Abstract Phytochemical investigations of the leaves and roots of Dalbergia tonkinensis led to the isolation of a new isoflavone glycoside derivative, isocaviunin 7-O-β-D-apiofuranosyl-(1 → 6)-β-D-glucopyranoside (1), and a new scalemic sesquiterpene lactone, 3,7-dimethyl-3-vinylhexahydro-6,7-bifuran-3(2H)-one (2), along with the previously known compounds 3-16, and nine other known compounds 17-25 were isolated from the leaves of Cratoxylum formosum. The chemical structures of the isolated compounds were elucidated by 1D- and 2D-NMR analyses as well as MS spectroscopic data. The results suggest that flavonoids are characteristic of both plants. In the DPPH radical scavenging assay, (3 R)-vestitol (5) and isoquercetin (24) possessed the strongest antioxidative IC50 values of 42.20 µg/mL and 45.63 µg/mL, respectively, and their values were comparable to that of the positive control catechin (IC50 42.98 µg/mL).

N , N ’-disubstitutedphenyl-4-ethoxyl benzene-1, 3-disulfonamides: design, synthesis, and evaluation of anti-platelet aggregation activity Abstract According to the bio-isosterism theory, a series of N, N’-disubstitutedphenyl-4-ethoxylbenzene-1, 3-disulfonamides (5a-p) were designed and synthesized by two steps of reactions including chlorosulfonation and ammonolysis. The structures of all compounds have been confirmed by IR, 1H-NMR, 13C-NMR, and ESI-MS spectra. The in vitro anti-platelet aggregation activities were evaluated by Born’s test induced by adenosine diphosphate (ADP) and arachidonic acid (AA), respectively. The biological evaluation results revealed that compound 5h had the lowest IC50 value (0.32 μM) and the highest inhibition rate (40.9 %) that of three positive control agents clopidogrel (0.41 μM, 23.5 %), aspirin (0.53 μM, 28.9 %), and picotamide (0.76 μM, 32.7 %). Afterwards, compounds with higher activities were selected to further study in vitro cytotoxicity via cell counting kit-8 (CCK-8) assay. The cytotoxicity results indicated that compound 5h had simultaneously the lowest cytotoxicity, while other compounds had no significant relationship between the anti-platelet activities and cytotoxicities. Based on above in vitro anti-platelet activity data, the SAR (Structure Activity Relationship) of the target compounds was preliminarily summarized. In general, N, N’-disubstitutedphenyl-4-ethoxylbenzene-1, 3-disulfonamides have the potential of further study and very likely become safer and more effective anti-platelet agents.

Synthesis and in vitro activities on anti-platelet aggregation of 4-methoxy-1,3-phthalamidesamides and benzenedisulfonamides Abstract Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. In order to discover novel compounds with anti-platelet aggregation activities, a series of novel 4-methoxy-1,3-phthalamidesamides (1a–1i) and a series of novel 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) were synthesized and their anti-platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP), arachidonic acid (AA), and Collagen. Those compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit-8 (CCK-8) assay. The inhibition rates of anti-platelet in vitro of five compounds 1g (39.45%), 2d (38.87%), 2g (38.55%), 2h (44.56%), and 2i (43.93%) were higher than that of two reference drugs picotamide (36.12%) and aspirin (38.45%) when ADP was selected as an inducer. The inhibition rates of seven compounds 1c (43.63%), 1d (40.02%), 1g (47.42%), 1i (40.45%), 2c (40.11%), 2d (40.45%), and 2i(49.05%) were higher than that of picotamide (34.89%) and aspirin (39.43%) when AA was selected as inducer. And the inhibition rates of five compounds 1d (47.22%), 1i (45.01%), 2d (38.74%), 2e (42.21%), and 2f (39.94%) were higher than picotamide (38.45%) and aspirin (37.08%) when collagen was selected as inducer. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L-929 cells. Therefore, 4-methoxy-1,3-phthalamidesamides (1a–1i) and 4-methoxy-1,3-benzenedisulfon-amides (2a–2i) have the potential to become a novel kind of anti-platelet drugs and deserve further study.

Synthesis and anti-inflammatory activity of 1,2-3-substituted 2a1,4,5-triazacyclopenta[cd]indene derivatives Abstract The present study reports the synthesis of 1,2-3-substituted-2a1,4,5-triazacyclopenta[cd]indene derivatives. The synthetic methodology includes some of the prominent reaction steps as specified in sequence (i) Bromination of acetophenones (ii) Condensation of 2-bromo-1-(substituted phenyl) ethanone derivatives with 2-aminopyrimidine, and (iii) Coupling of imidazo[1,2-a]pyrimidine derivatives with 1,2-diaryl/diaklylethynes. The structures of the newly synthesized derivatives have been determined by 1H NMR, 13C NMR, LC-MS, and IR spectral analysis. Furthermore, these derivatives were screened for their preliminary anti-inflammatory activities using Carrageenan induced paw edema test method. These promising screening results suggested a huge potential for the molecular diversity from present compounds that can be inflated to better lead candidates.

Potent anti-MRSA activity and synergism with aminoglycosides by flavonoid derivatives from the root barks of Morus alba , a traditional Chinese medicine Abstract Infections of clinical methicillin-resistant Staphylococcus aureus (MRSA) is a very tough public health problem and a challenge of new drug development. Nearly 90 Diels-Alder adducts (DAAs) have so far been isolated from Morus plants, but only a few of them have been evaluated for their anti-MRSA activities. To study the antibacterial compounds of DAAs from the root barks’ section of Morus alba L. and their synergism with antibacterial agents against clinical MRSA strains, bioassay-guided phytochemical methods were used to screen the active components. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were assayed through broth serial microdilution. The synergism were evaluated by checker board microdilution and dynamic time-kill experiments. Three DAAs (multicaulisin (1), sanggenon G (2) and albanin G (3)) were isolated and identified from M. alba root barks. They were determined with potent effect against MRSA isolates with MICs/MBCs at 2–8/16–128 mg/L. They also showed synergy with conventional antibacterial agents, especially the aminoglycosides, with fractional inhibitory concentration indices (FICIs) ranged from 0.19 to 0.50 and the dose reduction indices (DRIs) ranged from 16 to 2. The MRSA resistance to the antibiotics could be reversed by compounds 1–3. The dose-dependent bactericidal synergism against MRSA was observed as well. The study released for the first time the anti-MRSA synergism of DAAs from M. alba root barks with antibacterial agents and the reversal of MRSA resistance to aminoglycosides. The results may be valuable for further development of new antibacterial drugs and synergists against MRSA infections.

Synthesis and biological evaluation of novel disulfides incorporating 1,3,4-thiadiazole scaffold as promising antitumor agents Abstract In the present study, fourteen 2,5-disubstituted 1,3,4-thiadiazole derivatives containing disulfide group were prepared. The resulting compounds 7a–7n were identified by IR, NMR, MS, and elemental analysis. Their antiproliferative properties in vitro were studied employing standard CCK-8 assay against SMMC-7721, MCF-7, and A549 lines. Bioassay indicated that some compounds showed stronger antitumor effects than reference drugs PX-12 and 5-fluorouracil. Among these screened compounds, compound 7hshowed excellent biological activities in inhibiting SMMC-7721 cell proliferation with IC50 at 1.93 ± 0.08 μM. Compounds 7k and 7i manifested highly effective growth inhibitory activity versus MCF-7 cells, with IC50 at 3.04 ± 0.09 and 3.54 ± 0.17 μM, respectively. For A549 cells, compound 7m was found to have the highest antitumor potency with IC50 at 3.67 ± 0.13 μM.

QSAR-guided pharmacophore modeling and subsequent virtual screening identify novel TYK2 inhibitor Abstract Tyrosine Kinase 2 (TYK2) inhibition is of potential therapeutic value for treating autoimmune diseases. An elaborate ligand-based computational workflow was employed to explore structural requirements for TYK2 inhibition. Genetic function algorithm (GFA) was coupled to k-nearest neighbor (kNN) and multiple linear regression (MLR) analyses to search for predictive QSAR models based on optimal pharmacophore(s)/physicochemical descriptors combinations. QSAR-selected pharmacophores were validated by receiver operating characteristic (ROC) curve analysis and by comparison with crystallographic structures of known inhibitors complexed within the TYK2 binding pocket. Optimal QSAR models and their associated pharmacophore hypotheses were used to identify new TYK2 inhibitory leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit exhibited experimental anti-TYK2 IC50 of 7.1 µM.

Screening of 1,2-furanonaphthoquinones 1,2,3-1 H -triazoles for glycosidases inhibitory activity and free radical scavenging potential: an insight in anticancer activity Abstract In many cancer cells, glycoproteins show abnormal glycosylation patterns which have been associated with tumor initiation, progression, and metastasis. Thus, the glycosidases involved in glycoprotein maturation represent good targets for the development of new anticancer agents. In a previous report, we synthetized and evaluated the cytotoxic effect of a novel series of nor-β-lapachone tethered to 1H-1,2,3-triazoles (1,2-FNQT, 9a–r) against a panel of leukemia cell lines. Many 1,2-FNQT were active at low micromolar concentration and some were selective for cancer cells rather than normal ones. These results prompted us to investigate the mechanism of action that underlies their cytotoxic effect. Here, we tested if this effect could be attributed to the inhibition of cancer-related glycosidase activities, namely α-glucosidase and α-mannosidase. To evaluate enzyme selectivity, the same compounds were screened on other glycosidases of physiological relevance. In addition, we also studied the free radical scavenging activity of 1,2-FNQT, since redox metabolism plays a part in cancer development. Overall, the compounds were weak glycosidase inhibitors at 500 µM. The most active was 9i (IC50 = 413.7 µM) for α-glucosidase activity. In contrast, many of the compounds decreased more than 40% the content of DPPH, a free radical reagent, at 500 µM. This reduction was positively correlated with 1,2-FNQT cytotoxic potency, but only in KG1 cells (acute myelogenous leukemia). In conclusion, the cytotoxic effect of 1,2-FNQT on leukemic cells does not seem to be related to glycosidases inhibition, but may be, at least in part, due to their free radical scavenging activity.

Different reactivity to glutathione but similar tumor cell toxicity of chalcones and their quinolinone analogues Abstract Non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) onto two open-chain sulfonamide chalcones and two quinolinone-chalcone hybrids were studied to investigate the relationship between tumor cell cytotoxic activities and GSH-reactivities of the compounds. The consumption of the chalcones or the quinolinone-chalcone hybrids due to conjugation with GSH was evaluated by analytical high-performance liquid chromatography, and the formed diastereomeric adducts were identified by liquid chromatography–mass spectrometry. When the reaction was conducted with the open-chain chalcones, the equilibria were shifted towards formation of the respective GSH-conjugates. On the other hand, the cyclic chalcone derivatives with the quinolinone moiety were found to equilibrate to mixtures containing predominantly the reactants despite the strong electron withdrawing group present in the B-ring of the compounds. The observed opposite behavior can be rationalized by reduced thiol-reactivity of the quinolinone-chalcone hybrids and fast decomposition of their GSH-conjugates. A combined X-ray diffraction and theoretical approach were used to explain the observed difference in the reactivities towards GSH. However, structural differences did not influence tumor cell (SF-295, PC-3 and HCT-116) cytotoxicity of the evaluated compounds. Accordingly, the altered GSH-reactivity seems to be not a determining factor in the tested tumor cell cytotoxic activity of the investigated compounds.