β-Lactam Derivatives as Inhibitors of Human Cytomegalovirus Protease

Abstract

The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.

Potent β-Lactam Inhibitors of Human Cytomegalovirus Protease

“…IC 50 and EC 50 values were determined by previously published methods (Yoakim et al, 1998;Ogilvie et al, 1997;Bonneau et al, 1998). Each reported IC 50 value represents the mean of at least three determinations.…”

“…Isocyanates and carbamoyl chlorides that were not commercially available were prepared as previously reported (Yoakim et al, 1998). The secondary amines required for the formation of carbamoyl chlorides were easily made by condensation of the appropriate benzyl halide with methylamine (Yoakim et al, 1998).…”

“…The secondary amines required for the formation of carbamoyl chlorides were easily made by condensation of the appropriate benzyl halide with methylamine (Yoakim et al, 1998). Carbamoyl chlorides, which could not readily be prepared by this protocol, were synthesized as described (Figs 3 and 4).…”

“…Although HCMV protease was effectively inhibited, the 4-thioalkyl-β-lactam derivatives did not have the required stability in cell culture for good antiviral activity. Further to this study, we described novel monobactams bearing a benzyl group at C-4 and a tetrasubstituted urea at N-1, which had improved stabilities in cell culture (Yoakim et al, 1998). These compounds were modestly active in a plaque reduction assay despite their low micromolar potency in an enzymatic assay.…”

Novel Large‐Ring 1,3‐Bridged 2‐Azetidinones as Potential Inhibitors of Penicillin‐Binding Proteins

“…We selected RCM reaction (Ring Closing Metathesis) [18][19][20] as key-step for forming the large ring (Scheme 2), the required precursor being readily accessible by sequential functionalisation of nitrogen N1 and deprotected hydroxyl group on C5. We chose acylation reactions to introduce the two side-chains for the following reasons: (i) the synthetic easiness providing a rapid access to compounds of interest; (ii) the potential biological activities of the novel b-lactams, since N1-acylated compounds have been previously recognized as inhibitors of various proteases [21][22][23][24].…”