Synthesis, Anti-plasmodial and Anti-microbial Properties of Carvotacetone Analogues

Abstract

Resistance of plasmodia parasites, Cryptococcus neoformans and methicillin resistant Staphylococcus aureus to the available medications are a major cause of concern worldwide. This situation necessitates the requirement for the discovery of alternative anti-plasmodial, anti-fungal and anti-bacterial agents with different modes of action to stem the recurrence of these infections. This research aimed at synthesizing anti-plasmodial and anti-microbial carvotacetone analogues. The synthesis was accomplished starting from R-(-)-piperitone by Luche reduction, benzylation, Riley oxidation, acylation and N-alkylation. One novel carvotacetone, 3-O-benzylcarvotacetone (95) and two novel nitrogenous carvotacetone derivatives 4-benzyloxy-5-isopropyl-2-methylcyclohexa-1,3-dien-1-yl-pyrrolidine (102) and 3-benzyloxy-4-isopropylbenzylidene-3,4-dihydro-2H-pyrrole (103) were synthesized. Several other analogues [3-O-benzyl-piperitol (94), 3-benzyloxy-4-isopropylcyclohex-1-enecarbaldehyde (97) and seleno-bis(5-(benzyloxy)-4-isopropylcyclohex-1-ene-1-carbaldehyde (98)] are reported here for the first time. The synthesized analogues were characterised using different spectroscopic techniques (NMR, IR and MS). In vitro anti-plasmodial and anti-microbial assays were performed on the synthesized carvotacetone analogues. 3-Hydroxythymoquinone (96) exhibited anti-plasmodial activity (IC50 = 0.697 and 0.653 µg/mL) against P. falciparum D6 (chloroquine sensitive) and W2 (chloroquine resistant) strains, respectively. The acylated derivative of 96, 2-isopropyl-5-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl acetate (101) had an IC50 value of 3.37 and 3.19 µg/mL against D6 and W2 strains, respectively. In addition, analogue 96 and 97 exhibited anti-fungal activity against C. neoformans (IC50 = 3.11 and 15.77 µg/mL), the control drug fluconazole and amphotericin B had half maximal inhibitory concentration of 1.87 and 5.08 µg/mL. Derivative 101 demonstrated enhanced activity (IC50 = < 0.8 µg/mL) against C. neoformans and was moderately active (14.97 µg/mL) against MRSA bacteria. Derivative 103 demonstrated good in vitro anti-plasmodial activity with IC50 values of 0.306 µg/mL against D6 and 0.165 µg/mL against W2 strains of P. falciparum. Furthermore, this compound was found to have reduced toxicity with IC50 value > 4.76 µg/mL against the VERO cells. Moreover, derivative 103, showed anti-cryptococcal activity with an IC50 value of 3.098 µg/mL against the C. neoformans. From both the in vitro anti-plasmodial and anti-cryptococcal studies, compound 96 and 103 could be further optimized for development of alternative anti-malarial and anti-microbial drugs.