•Perfluorinated building blocks used in synthesis of heterocyclic scaffolds.•SNAr substitution reactions employed to deliver 6-benzimidazol-1-ylbenzothiophenes.•IC50 values of lead compounds were <1 μM against Trypanosoma brucei rhodesiense.Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 μM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

•A library of twelve fluoroaryl benzimidazoles prepared.•SNAr strategy allows rapid assembly of linked and macrocyclic heterocyclic structures.•X-ray crystal structures of fluorinated 21- and 24-membered macrocycles.•Three compounds exhibit micromolar inhibition of K-562 and MCF-7 cell lines.•Two compounds activate caspases leading to apoptosis.A small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis.Linked and macrocyclic fluoropyridylbenzimidazoles exhibit anti-cancer activity against breast carcinoma MCF-7 and leukemia K562 cell lines.

An unexpected azeto[2,3-c]quinolizinedione has been isolated during synthetic studies on the base catalyzed condensation of ethyl 6-methylpyridin-2(1H)-on-1-ylacetate with benzil. Closure of a fused four-membered azetidinone ring occurred when potassium hexamethyldisilazide was employed as the base. The structure of the product was confirmed by synchrotron X-ray crystallography. A possible mechanism for the formation of the product is considered.

Directed lithiation of η6-fluorobenzenetricarbonylchromium(0) and reaction with dialkyl disulfides affords η6-1,2-bis-alkylsulfanylbenzenetricarbonylchromium(0) complexes by electrophilic addition of an alkylthio group at C-2 of the benzene ring, and subsequent SNAr reaction with displacement of fluoride by the alkanethiolate generated in the first step. 1,2,3-tris-Alkylsulfanylbenzene complexes are formed as by-products. The structures of four of the new complexes have been confirmed by X-ray crystallography, one using synchrotron radiation.

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.