Acylating Agents as Enzyme Inhibitors and Understanding Their Reactivity for Drug Design

Abstract

A series of bicyclic trans-fused gamma-lactones and gamma-lactams have been previously described for the inhibition of human neutrophil elastase and as possible development candidates. During the discovery program, it had been assumed that their acylating power was due in part to the inherent strain energy in the bicyclic structure that was released upon ring opening. This is now shown not to be the case, and in fact, these compounds are no more reactive than simple but analogous gamma-lactams and gamma-lactones. The strain energy is not released in the transition state for alkaline hydrolysis or alcoholysis because the reaction proceeds with rate-limiting formation of the tetrahedral intermediate. A reactivity index of k(OH) is proposed as a simple guide to determine the usefulness of a potential inhibitor as an enzyme acylating agent.

The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion

“…(k inact /K i )/k OH or (k obs /[I])/k OH . 37,43 Remarkably, the 3,3-diethyl β-lactams 5e-j exhibit EREF values ca. 10 4 higher than those of their C-3 unsubstituted analogues 5b-d (Table 1).…”

“…Therefore we undertook reaction of inhibitor 5d with sodium methoxide in methanol, which has been reported as a good model reaction for the acylation of serine enzymes. 37,38 The product of this reaction was 3-benzylpyrimidine-2,4(1H,3H)-dione, 11, in 80% yield (Scheme 4).…”

“…37,39,40 Comparison of the k OH values presented in Table 1 reveals that the reactivity of β-lactams 5 correlates poorly to the pK a of the leaving group at C-4 of the β-lactam moiety. A poor correlation between log k OH values for the 3,3-diethyl series 5e-j and the pK a of the leaving group at C-4 was observed, corresponding to a β lg value of -0.05, indicating that there is essentially no change in the effective charge on the leaving group on going from the ground state to the transition state.…”

A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation

“…The observation that carbapenem‐derived lactones acylate serine β‐lactamases suggests that new classes of β‐lactamase inhibitors based on lactones are possible. In this regard, it is notable that the β‐lactone orlistat is an important medicine,21 and that lactone antibiotics (e.g., obafluorin)8 and inhibitors of serine proteases (and lactam derivatives thereof)22, 23 have been reported. Carbapenem‐derived β‐lactones thus represent a novel scaffold for β‐lactamase inhibition that, with optimization, may prove comparable in potency to the carbapenems.…”

From Amino Acids to Enantiopure Bicyclic Isoxazolidinylpyridin‐4(1H)‐ones through Intramolecular Nitrone Cycloadditions

“…[15] Elastases are current targets for medicinal chemistry; δ-lactams act by acylating a serine hydroxy group in the catalytic centre of a bacterial protease, with the same reactivity as β-lactam antibiotics. [16] …”