Oxidative aromatization, cytotoxic activity evaluation and conformational study of novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8[9H, 12H]-dione derivatives

In the present work, novel 7-aryl-10, 11-dihydro-7H-chromeno [4, 3-b]quinoline-6, 8[9H, 12H]-dione derivatives were synthesized by oxidation of 7-aryl-8, 9, 10, 12-tetrahydro-7H-chromeno[4, 3-b]quinoline-6, 8-diones in the presence of silica sulfuric acid/NaNO2 with yields of 64-74%. Cytotoxic activity of synthesized compounds was assessed on three different human cancer cell lines [K562, LS180, and MCF-7]. Synthesized compounds showed moderate cytotoxic activities. The most active one apeared to be 2e, containing a methoxy group on the meta position of phenyl ring [IC50 range in different cell lines: 11.1-55.7 Micro M]. Furthermore; comparison of the cytotoxic activity of these novel oxidized derivatives with non-oxidized counterparts revealed that oxidation of dihydropyridine ring to pyridine, improves the activity especially in LS180 cell line. Conformational analysis revealed that some conformational aspects of oxidized derivatives such as orientation of C7-aryl substitute were clearly different from non-oxidized ones

Anti-Helicobacter pylori activity and structure-activity relationship study of 2-alkylthio-5-[nitroaryl]-1,3,4-thiadiazole derivatives

Nitro-containing heteroaromatic derivatives structurally related to nitroimidazole [Metronidazole] are being extensively evaluated against Helicobacter pylori isolates. On the other hand, 1,3,4-thiadiazole derivatives have also demonstrated promising antibacterial potential. In present study, we evaluated anti-H. pylori activity of novel hybrid molecules bearing nitroaryl and 1,3,4-thiadiazole moieties. Anti-H. pylori activity of novel 5-[5-nitroaryl]-1,3,4-thiadiazole derivatives bearing different bulky alkylthio side chains at C-2 position of thiadiazole ring, were assessed against three different metronidazole resistant H. pylori isolates by paper disk diffusion method. Most of the compounds demonstrated moderate to strong inhibitory response especially at 25 micro g/disk. The structure-activity relationship study of the compounds demonstrated that introduction of different alkylthio moieties at C-2 position of thiadiazole ring alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring. The promising compound of this scaffold, bearing 1-methyl-5-nitroimidazole moiety at C-5 and alpha -methylbenzylthio side chain at C-2 position of thiadiazole ring, showed strong inhibitory response against metronidazole resistant H. pyloriisolates at 12.5 micro g/disk [the inhibition zone diameter at all evaluated concentrations [12.5-100 micro g/disk] is > 50 mm]. Novel 5-[5-nitroaryl]-1,3,4-thiadiazole scaffold bearing different C-2 attached thio-pendant moieties with promising anti-H. pylori potential were identified. Among different nitroheterocycles, 5-nitrofuran and 5-nitroimidazole moieties were preferable for the substitution at C-5 position of 1,3,4-thiadiazole ring. Introduction of different alkylthio side chains at C-2 position of central ring alter the inhibitory activity which is mainly dependent on the type of C-5 attached nitrohetercyclic ring

Fragment-based binding efficiency indices in bioactive molecular design: a computational approach to BACE-1 inhibitors

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 [BACE-1]. It is a membrane associated protein and is one of the main enzymes responsible for amyloid beta [A beta] production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the attention of scientists, because peptidic inhibitors have many pharmacokinetic problems. In the present study, several small molecule BACE-1 inhibitors were extracted from Brookhaven Protein Databank [PDB] and subjected to dissection analysis to achieve constructing fragments. Atom type, hybridization, and bond order were considered for generated constitutional fragments [simplified structures]. AutoDock version 4.2 was applied to dock various chemical fragments into BACE-1 active site. The benefits of such studies have been well revealed in previous reports. On the basis of obtained binding affinities, fragment-based ligand efficiency [LE] indices were estimated. These theoretical binding efficiencies were applied to further elucidate the key structural features of BACE-1 inhibitors. Typical results of the study were elucidated and we suggested the ways these findings might be beneficial to guide rational bioactive molecular developments. Our study confirmed that the evaluation of ligand-receptor interactions in terms of ligand efficiency indices [binding energy per atom and pK[i] per MW] could be a helpful strategy in structure-based drug discovery [SBDD] strategies