Disruption of Biofilm Formation and Quorum Sensing in Pathogenic Bacteria by Compounds from Zanthoxylum Gilletti (De Wild) P.G. Waterman.

Microbial resistance is facilitated by biofilm formation and quorum-sensing mediated processes. In this work, the stem bark (ZM) and fruit extracts (ZMFT) of Zanthoxylum gilletii were subjected to column chromatography and afforded lupeol (1), 2,3-epoxy-6,7-methylenedioxyconiferyl alcohol (3), nitidine chloride (4), nitidine (7), sucrose (6) and sitosterol-ß-D-glucopyranoside (2). The compounds were characterized using MS and NMR spectral data. The samples were evaluated for antimicrobial, antibiofilm and anti-quorum sensing activities. Highest antimicrobial activity was exhibited by compounds 3, 4 and 7 against Staphylococcus aureus (MIC 200 µg/mL), compounds 3 and 4 against Escherichia coli (MIC = 100 µg/mL) and compounds 4 and 7 against Candida albicans (MIC = 50 µg/mL). At MIC and sub-MIC concentrations, all samples inhibited biofilm formation by pathogens and violacein production in C. violaceum CV12472 except compound 6. Good disruption of QS-sensing in C. violaceum revealed by inhibition zone diameters were exhibited by compounds 3 (11.5 ± 0.5 mm), 4 (12.5 ± 1.5 mm), 5 (15.0 ± 0.8 mm), 7 (12.0 ± 1.5 mm) as well as the crude extracts from stem barks (16.5 ± 1.2 mm) and seeds (13.0 ± 1.4 mm). The profound inhibition of quorum sensing mediated processes in test pathogens by compounds 3, 4, 5 and 7 suggests the methylenedioxy- group that these compounds possess as the possible pharmacophore.

Structurally simple synthetic 1, 4-disubstituted piperidines with high selectivity for resistant Plasmodium falciparum.

BACKGROUND: Emergence of resistance to artemisinins and some of their combinations in chemotherapy of clinical malaria has intensified the search for novel safe efficacious antimalarial molecules. Fourteen synthetic 1, 4-disubstituted piperidines with simple molecular structures were evaluated in this study. METHODS: Antiplasmodial activity were determined against cultured chloroquine-sensitive 3D7 and resistant Dd2 strains of P. falciparum by in vitro parasite growth inhibition. A primary screen was done to identify active compounds by fluorescence microscopy followed by a secondary screen to determine IC50 and IC90 values of active compounds by the parasite lactate dehydrogenase assay. Cytotoxicity of active compounds was assessed using the MTT/formazan assay and selectivity indices (SIs) determined. Optical densities were analysed to obtain experimental results. RESULTS: The compounds produced 56 to 93% inhibition of parasite growth at 40 µg/mL. Eight compounds (2 ketone, 5 alcohol and one amine analogues) showed high activity (IC50s between 1 and 5 µg/mL). Nine compounds were highly selective for the parasite (SIs = 15 to 182). Three promising (alcohol) analogues were identified: [1-(4-fluorobenzyl) piperidin-4-yl] [4-fluorophenyl] methanol, (7), [1-(3, 4-dichlorobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (8) and [1-(4-bromobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (11) which were more active on the resistant strain (IC50 values between 1.03 to 2.52 µg/mL), than the sensitive strain (IC50 values between 2.51 to 4.43 µg/mL). CONCLUSIONS: The alcohol analogues were the most active and most selective for the parasite with three promising hit molecules identified among them, suggesting the hydroxyl group at C-7' in these alcohol analogues is contributing greatly to their antiplasmodial activity. Further exploration of the core structure using chemistry approaches and biological screening including in vivo studies in an animal model of malaria may yield important antimalarial leads.