Browsing by Author "Weaver, George W."

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    Design, Synthesis and Antitrypanosomal Activities of 2,6-Disubstituted-4,5,7-Trifluorobenzothiophenes
    (Elsevier, 2015-11-30) Bhambra, Avninder S.; Edgar, Mark; Elsegood, Mark R. J.; Li, Yuqi; Weaver, George W.; Arroo, R. R. J.; Yardley, Vanessa; Burrell-Saward, Hollie; Krystof, Vladimir
    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.
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    Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei
    (Elsevier, 2024-06-05) Bhambra, Avninder S.; Taylor, Annie; Hering, Moritz; Elsegood, Mark R. J.; Teat, Simon J.; Weaver, George W.; Arroo, R. R. J.; Kaiser, Marcel; Maeser, Pascal
    Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.
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    Novel Fluorinated Benzimidazole-Based Scaffolds and their Anticancer Activity in vitro
    (Elsevier, 2016-06-23) Bhambra, Avninder S.; Edgar, Mark; Elsegood, Mark R. J.; Horsburgh, Lynne; Kryštof, Vladimir; Lucas, Paul D.; Mojally, Mariam; Teat, Simon J.; Warwick, Thomas G.; Weaver, George W.; Zeinali, Fatemeh
    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.