Biological Evaluation of Compounds

Compounds 1, 2, 3, 5, 8, 9 and 10 from the top ten compounds were sent to have their efficacy evaluated against Plasmodium falciparum in-vitro at Syngene.

All values in nanoMolar.

They were repeated twice owing to poor quality statistics in the first assay:

 The results didn't reveal any 'killer' compounds but provided the team with some important SAR information.

• Aliphatic groups in top right of the molecule kill activity.
• Unsubstituted aromatic group in top right of the molecule kill activity.
• Substituted pyridines more potent than unsubstituted.
• Replacing alcohol side chain with methanol kills activity.
• Polar group in benzylic position of side chain improves activity but mono-methylation of benzylic amine kills activity.

The team are currently digesting the latest data and a new set of target molecules will be proposed later today and discussed in an online meeting to be arranged next week. 

General assay principle:
"This protocol assesses compound efficacy against Plasmodium falciparum in-vitro. This assay is using [3H]-hypoxanthine incorporation or DNA labeling by SYBR Green as a markers of parasite growth. 
This procedure is designed for use with culture adapted P. falciparum strains or clones only. On one 96-well plate typically 03 drugs are tested in duplicate. Standard strains: Plasmodium falciparum, NF54 (sensitive to all known drugs), Plasmodium falciparum, K1 (chloroquine and pyrimethamine resistant). The assay can be performed in dose response mode (12 concentrations in duplicate, 24 data points) which allows determining IC50, or in single concentration mode (one concentration in triplicate, 3 data points) which allows determining the percentage of growth inhibition.
For more information, see Desjardins et al. (Antimicrob. Agents Chemother., 16(6), 710, 1979)."

(Post originally authored by Alice Williamson)