Metal- and photocatalyst-free approach to visible-light-induced acylation of quinoxalinones.

A transition-metal- and photocatalyst-free photochemical reaction was successfully developed for the direct acylation of quinoxalin-2(1H)-ones, which was enabled by the formation of electron donor-acceptor (EDA) complexes. The use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the electron donor allows efficient and operationally simple access to a series of C3-aroylated and acylated quinoxalin-2(1H)-ones with moderate to good yields.

A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases.

Virtual screening a collection of ~ 25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100 ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20 ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted ΔGbind values of - 38.1 and - 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of - 34.4 and - 25.8 kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100 ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the ΔGbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability.

Discovery of potent antiproliferative agents from selected oxygen heterocycles as EGFR tyrosine kinase inhibitors from the U.S. National Cancer Institute database by in silico screening and bioactivity evaluation.

A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC50 values between 0.95 and 17.71 µM against overexpressed EGFR-TK cancer cell lines: A431 and HeLa. NSC107228 displayed the strongest antiproliferative effects with IC50 values of 2.84 and 0.95 µM against A431 and HeLa cancer cell lines, respectively. Three compounds, NSC81111, NSC381467 and NSC114126 inhibited EGFR-TK with IC50 values between 0.15 and 30.18 nM. NSC81111 was the best inhibitor with IC50 = 0.15 nM. Molecular docking analysis of the 3 compounds predicted hydrogen bonding and hydrophobic interactions with key residues were important for the bioactivities observed. Furthermore, calculations of the physicochemical properties suggest the compounds are drug-like and are potentially active orally.

Visible-light-mediated decarboxylative alkylation of 2-pyridone derivatives via a C3-selective C-H functionalization.

A direct C-H functionalization approach to access C3-alkylated 2-pyridone derivatives is reported. This study utilizes N-hydroxyphthalimide (NHPI) esters of various carboxylic acids as sources of alkyl radicals by reductive cleavage under photocatalytic reaction conditions. The carbon-carbon bond formation occurred site-selectively at C3 of 2-pyridone to give the desired products in moderate to good yields. This method enables a faster access to C3-alkylated pyridone compounds which can be applied to the synthesis of small molecule drugs.

Identification of new 3-phenyl-1H-indole-2-carbohydrazide derivatives and their structure-activity relationships as potent tubulin inhibitors and anticancer agents: A combined in silico, in vitro and synthetic study.

Virtual screening of commercially available molecular entities by using CDRUG, structure-based virtual screening, and similarity identified eight new derivatives of 3-phenyl-1H-indole-2-carbohydrazide with anti-proliferative activities. The molecules were tested experimentally for inhibition of tubulin polymerisation, which revealed furan-3-ylmethylene-3-phenyl-1H-indole-2-carbohydrazide (27a) as the most potent candidate. Molecule 27a was able to induce G2/M phase arrest in A549 cell line, similar to other tubulin inhibitors. Synthetic modifications of 27a were focussed on small substitutions on the furan ring, halogenation at R1 position and alteration of furyl connectivity. Derivatives 27b, 27d and 27i exhibited the strongest tubulin inhibition activities and were comparable to 27a. Bromine substitution at R1 position showed most prominent anticancer activities; derivatives 27b-27d displayed the strongest activities against HuCCA-1 cell line and were more potent than doxorubicin and the parent molecule 27a with IC50 values <0.5 µM. Notably, 27b with a 5-methoxy substitution on furan displayed the strongest activity against HepG2 cell line (IC50 = 0.34 µM), while 27d displayed stronger activity against A549 cell line (IC50 = 0.43 µM) compared to doxorubicin and 27a. Fluorine substitutions at the R1 position tended to show more modest anti-tubulin and anticancer activities, and change of 2-furyl to 3-furyl was tolerable. The new derivatives, thiophenyl 26, displayed the strongest activity against A549 cell line (IC50 = 0.19 µM), while 1-phenylethylidene 21b and 21c exhibited more modest anticancer activities with unclear mechanisms of action; 26 and 21c demonstrated G2/M phase arrest, but showed weak tubulin inhibitory properties. Molecular docking suggests the series inhibit tubulin at the colchicine site, in agreement with the experimental findings. The calculated molecular descriptors indicated that the molecules obey Lipinski's rule which suggests the molecules are drug-like structures.

Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones.

Aliphatic ketones containing a chloride and alkene were heated with hydroxylamine to promote cascade, tandem condensation to oximes, cyclization to nitrones, and 1,3-dipolar cycloaddition to tricyclic isoxazolidines as single stereoisomers. Single regioisomers were obtained when three atoms linked the ketone and dipolarophile to give five-membered rings but mixtures resulted with four atoms in the tether unless a terminal ester was located on the alkene. The N-O bond in the products could be reduced to give spirocyclic amines and diamines.

Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition.

Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine.

Synthesis of the tricyclic core of manzamine A.

An efficient synthetic approach to the core structure of the manzamine alkaloids is reported, particularly in relation to incorporating a one-carbon unit in ring B from which the aldehyde in ircinal A or the beta-carboline unit in manzamine A could potentially be generated. The key steps involve a Johnson-Claisen rearrangement, enolate alkylation, dithiane alkylation and a stereoselective intramolecular dipolar cycloaddition of an azomethine ylide, which provided the desired tricyclic ABC core structure.