Development of Anti-Wolbachia Treatment: AWZ1066S

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Researchers from the University of Liverpool and Liverpool School of Tropical Medicine have developed AWZ1066S, the first novel fully synthetic, rationally designed anti-Wolbachia drug. Optimized from a 10,000-compound library, this highly potent, first-in-class drug has the potential to significantly impact current global onchocerciasis and lymphatic filariasis elimination programs and reduce elimination time frames from decades to years.

During this optimization process, the thienopyrimidine core (orange) of the initial hit molecule was systematically transformed into a quinazoline scaffold (blue, AWB158) and ultimately into an azaquinazoline derivative AWZ1066S (red). These modifications successfully addressed the metabolic instability of the original scaffold while enhancing potency. Starting from the initial hit molecule, the potency of AWZ1066S was enhanced by 130-fold, with EC₅₀ values improving from 328 nM to 2.5 nM.

A key structural modification involved substituting the electron-donating methoxy (OMe) group in HIT 1 with an electron-withdrawing trifluoromethyl (CF₃) group in AWB124. This substitution not only introduces steric strain due to the increased bulkiness of CF₃ but also facilitated favourable hydrogen bonding through fluorine atoms, further strengthening target binding interactions.

The potency and selectivity of AWZ1066S against Wolbachia parasites can be attributed to its distinct structural features, including:

• The lipophilic electron-withdrawing CF₃ group at the 4-position of the side chain
• The nitrogen substitution at the 8-position of the azaquinazoline core
• The S-enantiomer of the methyl group located at the 2-position of the morpholinyl side chain

These combined modifications contribute significantly to enhanced permeability, metabolic stability, and overall efficacy.

W. D. Hong, F. Benayoud, G. L. Nixon, L. Ford, K. L. Johnston, R. H. Clare, A. Cassidy, D. A. N. Cook, A. Siu, M. Shiotani, P. J. H. Webborn, S. Kavanagh, G. Aljayyoussi, E. Murphy, A. Steven, J. Archer, D. Struever, S. J. Frohberger, A. Ehrens, M. P. Hübner, A. Hoerauf, A. P. Roberts, A. T. M. Hubbard, E. W. Tate, R. A. Serwa, S. C. Leung, L. Qie, N. G. Berry, F. Gusovsky, J. Hemingway, J. D. Turner, M. J. Taylor, S. A. Ward and P. M. O’Neill, Proceedings of the National Academy of Sciences, 2019, 116, 1414-1419.