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Journal: Archiv der Pharmazie


A new scaffold of hydrazothiazoles has been designed as monoamine oxidase (MAO) inhibitors combining the hydrazine moiety of iproniazid and the thiazole nucleus of glitazones, a class of peroxisome proliferator-activated receptor (PPAR)γ agonists recently co-crystallized with human MAO-B. The resulting derivatives were synthesized and assayed to evaluate their in vitro activity against both the A and B isoforms of hMAO. All compounds were shown to be selective hMAO-B inhibitors with IC(50) values in the low micromolar/high nanomolar range. Such results suggest that the hydrazothiazole scaffold could be considered as an interesting pharmacophore for the future design of new lead compounds as coadjuvants for the treatment of neurodegenerative diseases.

Concepts: Peroxisome proliferator-activated receptor, Neuroscience, Oxidase, Serotonin, Nuclear receptor, Monoamine oxidase, Monoamine oxidase inhibitor, Monoamine oxidase B


In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50)  = 69.3 µM) and Leishmania brasiliensis (IC(50)  = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50)  = 99.9 µM for L. amazonensis and IC(50)  = 90.5 µM for L. braziliensis) and 3 (IC(50)  = 122.9 µM for L. amazonensis and IC(50)  = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.

Concepts: Fibroblast, In vitro fertilisation, In vitro, Chemical compound, Piper aduncum, Piper


In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8(S) , 11(S) , and 12(S) showed anti-HIV-1 activity with a 50% inhibitory concentration (IC(50) ) = 123.8 µM (selectivity index, SI > 3), IC(50)  = 12.1 µM (SI > 29), IC(50)  = 17.4 µM (SI > 19), respectively. Enantiomers 8® , 11® , and 12® were inactive against the HIV-1 strain III(B) . Hydrazones 8(S) , 11(S) , and 12(S) which were active against HIV-1 wild type showed no inhibition against a double mutant NNRTI-resistant strain (K103N;Y181C). Molecular docking calculations of R- and S-enantiomers of 8, 11, and 12 were performed using the hydrazone-bound novel site of HIV-1 RT.

Concepts: Gene, Amino acid, Virus, Influenza, Computational chemistry, Enzyme inhibitor, Molecular modelling, Molecular mechanics


The oncoprotein cytotoxic associated gene A (CagA) of Helicobacter pylori plays a pivotal role in the development of gastric cancer, so it has been an important target for anti-H. pylori drugs. Conventional drugs are currently being implemented against H. pylori. The inhibitory role of plant metabolites like curcumin against H. pylori is still a major scientific challenge. Curcumin may represent a novel promising drug against H. pylori infection without producing side effects. In the present study, a comparative analysis between curcumin and conventional drugs (clarithromycin, amoxicillin, pantoprazole, and metronidazole) was carried out using databases to investigate the potential of curcumin against H. pylori targeting the CagA oncoprotein. Curcumin was filtered using Lipinski’s rule of five and the druglikeness property for evaluation of pharmacological properties. Subsequently, molecular docking was employed to determine the binding affinities of curcumin and conventional drugs to the CagA oncoprotein. According to the results obtained from FireDock, the binding energy of curcumin was higher than those of amoxicillin, pantoprazole, and metronidazole, except for clarithromycin, which had the highest binding energy. Accordingly, curcumin may become a promising lead compound against CagA+ H. pylori infection.

Concepts: Pharmacology, Cancer, Bacteria, Stomach, Helicobacter pylori, Helicobacter, Clarithromycin, Gastritis


A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC50 values (0.25-1.7 µM) were lower than that of indomethacin (IC50  = 9.47 µM) and somewhat higher than that of celecoxib (IC50  = 0.071 µM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02-74.03 µM, while the IC50 of the reference zileuton was 0.83 µM. The most active compound 4c (4-chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.

Concepts: Spectroscopy, Cell, Cancer, Amine, Proton, Cyclooxygenase, Chemical element, Deuterium


The stereochemistry of non-enzyme catalyzed nucleophilic addition of GSH to 4'-hydroxychalcone 1 and its bis-Mannich derivative 2 was investigated at different pH values (pH 3.2, 6.1, 7.4, and 8.0). The stereochemical outcome of the reactions was evaluated by HPLC-UV-Vis method. Under strongly acidic conditions (pH 3.2), an unexpected diastereoselective addition of GSH onto the bis-Mannich derivative 2 was observed. Such a selectivity could not be observed in the similar reaction of 2 with N-acetylcysteine. The observed stereoselectivity can be rationalized by ion-pair formation between the protonated Mannich nitrogens and the deprotonated GSH(glutamate)-carboxylate. To the best of our knowledge, this is the first example of reagent-induced asymmetric induction in Michael-type additions of thiols.


B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton’s tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib. Constantly emerging agents exhibiting superior efficacy and safety in preclinical and clinical studies provide promising therapeutics for the treatment of B cell malignancies.


A series of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives (3am) was synthesized and evaluated for their in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC50  < 1 μM) were evaluated in vivo for their anti-inflammatory potential by the carrageenan-induced rat paw edema method. Out of 13 newly synthesized compounds, 3a, 3b, 3d, 3g, 3j, and 3k were found to be the most potent COX-2 inhibitors in the in vitro enzymatic assay, with IC50 values in the range of 0.06-0.71 μM. The in vivo anti-inflammatory activity of these six compounds (3a, 3b, 3d, 3g, 3j, and 3k) was assessed by the carrageenan-induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti-inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX-2, to understand the binding mechanism of these inhibitors to the active site of COX-2.


The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a-h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.


A series of compounds bearing quinoline-imidazole (8a-e, 9a-e, 10a-e, 11a-e, and 12a-e) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC-3, HepG2, and MCF-7 cells by the MTT method, with NVP-BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC-3 cells, with half-maximal inhibitory concentration (IC50 ) values of 2.42 ± 1.02 µM, 6.29 ± 0.99 µM, and 5.11 ± 1.00 µM, respectively, which was equal to NVP-BEZ235 (0.54 ± 0.13 µM, 0.36 ± 0.06 µM, 0.20 ± 0.01 µM). Besides, the IC50 value of 12a against the cell line WI-38 (human fetal lung fibroblasts) was 32.8 ± 1.23 µM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K-Akt-mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP-BEZ235, suggesting there may be some other mechanisms of action. The structure-activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C-6 of the quinoline ring was replaced by a bromine atom.