Edinburgh Napier University

  Parasitic helminth infections of livestock are a threat to the health and production of livestock, crops and to human health. One third of the world’s animal population was affected in 2015 by helminth infestations causing severe morbidity. The shortfall of new drugs against nematode parasites and the resistance hazard represents an urgent need for the development of novel anti-parasitic drugs with effective delivery to the target site. It is hypothesised that the toxic efficacy and selectivity of anthelmintic drugs can be improved using prodrug forms that possess intracellular drug targeting moieties that can circumvent resistance mechanisms.
A series of novel targeted anthelmintic candidate drugs have been synthesized, based on a colchicine (Col) core; code-named: AM1 (Col-prolinol), AM3 (Col-4hydroxypiperidine), AM4 (Col-(R)-3-pyrrolidinol), AM5 (Col-Boc-aminopyrrolidine) and AM6 (Col-aminopyrrolidine), these compounds are broadly tubulin targeting aminocolchicine derivatives. Amino-colchicines were then conjugated with a lipophilic, cationic targeting moiety TPP (triphenylphosphonium) ion that has potential to bypass resistance and achieve selectivity by direct and fast accumulation in the matrix of mitochondria. Novel prodrugs AM2 (Col-prolinol-TPP), AM7 (Col-aminopyrrolidineTPP), AM8 (Col-4-hydroxypiperidine-TPP), AM9 (Col-(R)-3-pyrrolidinol-TPP) are ester-linked triphenylphosphonium butanoyl (TPP) conjugates of amino-colchicines AM1, AM6, AM3 and AM4 respectively that are designed to not only pass through cell membranes and localise in the mitochondria but also facilitate drug cellular uptake by avoiding p-glycoprotein-type mediated efflux mechanisms. All novel compounds have been characterised by high resolution mass spectrometry and 1H and 13C NMR spectroscopy. Preliminary biological evaluation of AM1 and AM2 was carried out by treatment of the C. elegans non-parasite model organism. Results demonstrated that AM2 (100µM) showed significant toxicity against C. elegans at an incubation time of 22h. Physicochemical properties of these novel agents has been described in terms of distribution coefficient log D values, that showed they are lipophilic in nature and should have the ability to cross lipid bilayers and mitochondrial membrane. Preliminary molecular docking studies also demonstrated binding affinity of AM6 (Colaminopyrrolidine) with tubulin. These novel prodrugs have the potential to be developed as effective anthelmintic agents in the treatment of parasitic helminth disease.