DESIGN, SYNTHESIS AND EVALUATION OF A NOVEL SERIES OF SPIROKETALS BASED ON THE STRUCTURE OF THE ANTIBACTERIAL GYRASE INHIBITOR NOVOBIOCIN

Molecular modelling has been used in conjunction with crystallographic and biological data in an attempt to design compounds that mimic the structure and activity of the coumarin antibiotic novobiocin 2, Calcul ations on four conformations of a 6,6-spiroketal system 8-11 suggest t hat whilst 9 should be the lowest energy, 8 should also be readily acc essible and this conformation overlays well with the coumarin and suga r rings of novobiocin, Incorporation of key hydroxy and carbamate grou ps onto the cyclohexane and a hydrogen bond acceptor onto the aromatic ring suggest 12a as the initial target, The crystal structure of a mo del compound 24 shows the conformation illustrated in 9 and thus suppo rts the molecular modelling, However, the crystal structure of novobio cin bound to a 24 kD fragment of gyrase B, the target of the coumarin antibiotics, reveals that it is the lactone carbonyl rather than the G ory group which is responsible for a key interaction with an Arg resid ue and consequently the carboxy group in 12a is misplaced as a corresp onding H-bond acceptor, Subsequently, compounds incorporating an extra aromatic (as in 13a) or heteroaromatic ring (as in 45) bearing an H-b ond acceptor, along with the extra dimethyl groups on the cyclohexane ring, have been designed. Models of these structures overlay convincin gly with novobiocin bound to 24 kD gyrase B, Versatile synthetic route s have been developed allowing these compounds and the underlying hypo theses to be tested, Unfortunately, none of the compounds demonstrates significant enzyme or antibacterial activity, which we attribute to a combination of features, including the lack of a replacement for the noviose methoxy group and the failure to achieve a good stacking (char ge transfer) interaction with Arg-76.