Dual targeting of mitochondrial Lon peptidase 1 and chymotrypsin-like protease by small molecule BT317, as potential therapeutics in malignant astrocytoma.

Malignant astrocytomas are aggressive glioma tumors characterized by extensive hypoxia-induced, mito-chondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness and increased invasiveness. Mitochondrial Lon Peptidase I (LonP1) overexpression and increased CT-L proteasome inhibitors activity are the biomarkers of aggressive high grade glioma phenotype, poor prognosis and found to be associated with recurrence and poor patient survival, and drugs targeting either LonP1 or the CT-L activity have anti-glioma activity in pre-clinical models. We here for the first time introduced and evaluated a novel small molecule, BT317, derived from coumarinic compound 4 (CC4) using structure-activity modeling which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain-of-function and loss-of-function genetic models, we dis-covered that BT317 is more effective than the individual LonP1 or CT-L inhibition in increasing reactive oxy-gen species (ROS) generation and inducing apoptosis in high-grade astrocytoma lines. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In orthotopic xenograft, patient derived glioma models, BT317 was able to cross the blood-brain barrier, to show selective activity at the tumor site and to demonstrate therapeutic efficacy both as a single agent and in combination with TMZ. BT317 defines an emerging class of dual LonP1, and CT-L proteasome inhibitors exhibited promising anti-tumor activity and could be a promising candidate for clinical translation in the space of malignant astrocytoma therapeutics.

Dual Role of Glyoxal in Metal-Free Dicarbonylation Reaction: Synthesis of Symmetrical and Unsymmetrical Dicarbonyl Imidazoheterocycles.

A practical and efficient method has been developed for the dicarbonylation of imidazoheterocycles using glyoxals as dicarbonyl precursors under metal-free conditions in acetic acid. A series of symmetrical and unsymmetrical dicarbonyl imidazoheterocycles was synthesized in good yields. Aryl and alkyl glyoxals also demonstrated excellent reactivity under similar reaction conditions and delivered corresponding dicarbonyl imidazoheterocycles in high yields. It is believed that the glyoxal plays a dual role both as a dicarbonyl source and as an oxidant in this transformation. A probable mechanistic pathway has been proposed based on control experiments and electrospray ionization high-resolution mass spectrometry analysis.

Copper and palladium-catalyzed sequential reactions: one-pot synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-ones.

A highly efficient protocol has been developed for the synthesis of diversely substituted isoindolo[2,1-b]isoquinolin-7(5H)-ones through sequential Cu(ii)-catalyzed Sonogashira coupling, intramolecular hydroamidation followed by palladium-catalyzed ligand-free Heck reaction. Good to excellent yields (41-94%) were observed with excellent substrate scope and functional group tolerance. The developed method represents a practical strategy for the construction of bioactive isoindolo[2,1-b]isoquinolin-7(5H)-ones.

Metal-free synthesis of aminomethylated imidazoheterocycles: dual role of tert-butyl hydroperoxide as both an oxidant and a methylene source.

A novel and efficient aminomethylation approach has been developed for the regioselective functionalization of imidazoheterocycles under metal-free conditions. A wide range of imidazoheterocycles and 2/4-aminoazaheterocycles successfully provided corresponding aminomethylated imidazoheterocycles in moderate to excellent (33-80%) yields. The isotopic labelling study suggested that TBHP played a dual role as both an oxidant and a methylene source in this transformation. The developed protocol follows a radical pathway which is supported by radical trapping experiments.

Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity.

A new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C-N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative (Escherichia coli, Pseudomonas putida, and Salmonella typhi) and two Gram positive (Bacillus subtilis, and Staphylococcus aureus) bacteria. Among all tested compounds, 8ga, 8gc, and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4-8 µg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga, 8gc, and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8-16 µg/mL) against both strains. The bactericidal assay by propidium iodide and live-dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds (8ga, 8gc, and 8gd) showed their safety profile toward human blood cells.

Synthesis of novel azole-fused quinazolines via one-pot, sequential Ullmann-type coupling and intramolecular dehydrogenative C-N bonding.

An efficient one-pot sequential procedure is described for the synthesis of novel azole-fused quinazolines through Pd/Cu co-catalyzed, Ullmann-type coupling followed by cross dehydrogenative coupling of various azoles such as 1H-imidazole, 1H-benzimidazole and 1H-1,2,4-triazole with 2-(2-bromophenyl)-1H-imidazole/benzimidazoles. The developed strategy has offered good yields (52-81%) of diverse N-fused tetra-, penta- and hexa-cyclic frameworks in a single step.