The 10 most-cited articles in Archiv der Pharmazie, 2017

Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body. Benzimidazole is an organic compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 8.8 million deaths of which 70% of the cases were from low- and middle-income countries. In the efforts to develop suitable anticancer drugs, medicinal chemists have focussed on benzimidazole derivatives. This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure-activity relationships (SAR).

Novel series of phthalazine derivatives 6–11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT‐116 human colon adenocarcinoma and MCF‐7 breast cancer cells, targeting the VEGFR‐2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF‐7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR‐2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR‐2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict…

Three series of imidazolidinium ligands (NHC precursors) substituted with 4‐vinylbenzyl, 2‐methyl‐1,4‐benzodioxane, and N‐propylphthalimide were synthesized. N‐Heterocyclic carbene (NHC) precursors were prepared from N‐alkylimidazoline and alkyl halides. The novel NHC precursors were characterized by 1H NMR, 13C NMR, FTIR spectroscopy, and elemental analysis techniques. The enzymes inhibition activities of the NHC precursors were investigated against the cytosolic human carbonic anhydrase I and II isoenzymes (hCA I and II) and the acetylcholinesterase (AChE) enzyme. The inhibition parameters (IC50 and Ki values) were calculated by spectrophotometric method. The inhibition constants (Ki) were found to be in the range of 166.65–635.38 nM for hCA I, 78.79–246.17 nM for hCA II, and 23.42–62.04 nM for AChE. Also, the inhibitory effects of the novel synthesized NHCs were compared to acetazolamide as a clinical CA isoenzymes inhibitor and tacrine as a clinical cholinergic enzymes inhibitor.

The design, synthesis, and investigation of antitumor and anti-lipase activities of some coumarin-triazole hybrid molecules are reported. The synthesis of these hybrid molecules was performed under microwave irradiation and conventional heating procedures. The newly synthesized hybrid molecules were investigated as inhibitors against four tumor cell lines (BT20 human breast carcinoma, SK-Mel 128 melanoma, DU-145 prostate carcinoma, and A549 lung carcinoma) and porcine pancreatic lipase (PPL). Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively, at a concentration of 10 μM.

Breast and cervical cancers are the most common gender‐specific cancers affecting women worldwide. In this investigation, we highlighted the synthesis, VEGFR‐2 and p38α MAPK inhibitory activity of new series of fluorinated coumarin‐based derivatives featuring a variety of bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position. The bioactive inhibitors were further assessed for their anti‐proliferative effect against human MCF‐7 breast cancer and HeLa cervical cancer cell lines, respectively. Most of the tested compounds showed potent preferential inhibition effects against human VEGFR‐2 and remarkable anticancer activities in the human breast cancer cell line MCF‐7. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR‐2 (94% inhibition) and they were the most potent anticancer agents toward MCF‐7 cancer cells with IC50 values of 7.90, 8.28, and 8.30 μg/mL, respectively. Compound 13 inhibited p38α MAPK phosphorylation with a significant reduction in % cell viability against HeLa cancer cells at 10 and 30 µM. Docking…

The synthesis and evaluation of the anti‐inflammatory activity of some structure hybrids comprising basically the 5‐hydroxy‐3‐methyl‐1‐phenyl‐4‐substituted‐1H‐pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3‐c]pyrazoles, is described. According to thein vivoresults and a comprehensive structure–activity relationship study, five analogs (5,10,17,19, and27) displayed remarkable anti‐inflammatory profiles showing distinctive % protection and ED50values, especially10and27(ED5035.7 and 38.7 μmol/kg, respectively) which were nearly equiactive to celecoxib (ED5032.1 μmol/kg). Compounds10,17, and27exhibited distinctive COX‐2 inhibition with a noticeable COX‐2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally,5,10,17,19, and27proved to be gastrointestinal tract safe (0–20% ulceration) and non‐toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, thein vivoED50values for the most potent five derivatives…

values for in vitro inhibition of the enzymes cyclooxygenase 1/2 (COX-1, COX-2) and 5-lipoxygenase (5-LOX) were investigated. All compounds were tested for their in vivo anti-inflammatory and analgesic potentials using diclofenac sodium as a reference standard. Compounds 4, 11, 17, 20, 21, 26, and 27, which showed good analgesic and/or anti-inflammatory activities, were also evaluated for their ability to inhibit tumor necrosis factor (TNF)-α production, myeloperoxidase and proteinase, beside their antioxidant activity. Collectively, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic, and antioxidant activities, beside dual COX-2 and 5-LOX inhibition. Among these, compound 26 showed high selectivity for in vitro COX-1/COX-2 inhibition, whereas the analogs 11 and 17 noticeably ameliorated the TNF-α level by 85.19 and 97.71%, respectively. A molecular docking study was performed to investigate the possible binding mode of compounds 11, 17, and 26 with the active sites of the COX-2 and 5-LOX enzymes, where they showed nearly the same binding pattern as that of…

In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose‐4B‐l‐tyrosine‐sulfanilamide affinity gel chromatography. Secondly, a series of new tetrabromo chalcone derivatives containing 4,7‐methanoisoindol‐1,3‐dione (2a–i) were synthesized from the addition of Br2 to related chalcone derivatives (1a–i). The structures of the new molecules (2a–i) were confirmed by means of 1H NMR, 13C NMR and elemental analysis. Finally, the inhibitory effects of 2a–i on CA activities were investigated using the esterase method under in vitro conditions. The compounds 2a–i exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 11.30–21.22 nM against hCA I and in the range of 8.21–12.86 nM against hCA II. Our findings suggest that the new compounds 2a–i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained Ki values of 34.50 and 28.93 nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays,…

Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and α-glucosidase in…

Abstract A novel series of coumarin‐thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1H NMR, 13C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60‐cell line panel according to the US NCI‐DTP protocol or a selection of human tumor cell lines: breast cancer (MCF‐7), liver cancer (HepG‐2), and colorectal cancer (HCT‐116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 × 105 M−1. Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 × 105, 3.96 × 105, and 3.51 × 105 M−1, respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60‐cell line panel, the leukemia…