Example:

Optimisation of 3-Methoxybenzamide leading to potent antibacterials with in vivo efficacy

Problem:

High-throughput screens had failed to identify optimisable and progressible compounds. Alternative more advantageous starting points were required.

Solution:

Lloyd Czaplewski realised that a literature compound, 3-Methoxybenzamide, which was descibed as a weak inhibitor of FtsZ was a good starting point for optimisation. It was on-target & was able to penetrate the bacterial cell. An effective medicinal chemistry Lead Optimisation project led to compounds with in vivo efficacy & competitive pharmaceutical properties.

Reference Link:

Haydon DJ, Stokes NR, Ure R, Galbraith G, Bennett JM, Brown D, Baker PJ, Barynin VV, Rice DW, Sedelnikova SE, Heal JR, Sheridan JM, Aiwale ST, Chauhan PK, Srivastava A, Taneja A, Collins I, Errington J, Czaplewski LG. A novel inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321, 1673-1675.

Czaplewski LG, Collins I, Boyd EA, Brown D, East SP, Gardiner M, Fletcher R, Haydon DJ, Henstock V, Ingram P, Jones C, Noula C, Kennison L, Rockley C, Rose V, Thomaides HB, Ure R, Whittaker M Stokes NR. Antibacterial alkyloxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorganic Medicinal Chemistry Letters 2009; 19(2):524-7.

Haydon DJ, , Bennett JM, Brown D, Collins I, Lancett P, Stokes NR, Macdonald R, Chauhan PK, Sutariya JK, Nayal N, Srivastava A, Beanland J, Hall R, Henstock V, Noula C, Rockley C, Czaplewski LG. (2010). Building an antibacterial with in vivo efficacy: synthesis and characterisation of potent inhibitors of the bacterial cell-division protein FtsZ with improved pharmaceutical properties. J. Med Chem. 53, 3927-3936.