Synthesis, hydrolysis rates, supercomputer modeling, and antibacterial activity of bicyclic tetrahydropyridazinones

Abstract

Bicyclic tetrahydropyridazinones, such as 13, where X are strongly electron-withdrawing groups, were synthesized to investigate their antibacterial activity. These delta-lactams are homologues of bicyclic pyrazolidinones 15, which were the first non-beta-lactam containing compounds reported to bind to penicillin-binding proteins (PBPs). The delta-lactam compounds exhibit poor antibacterial activity despite having reactivity comparable to the gamma-lactams. Molecular modeling based on semiempirical molecular orbital calculations on a Cray X-MP supercomputer, predicted that the reason for the inactivity is steric bulk hindering high affinity of the compounds to PBPs, as well as high conformational flexibility of the tetrahydropyridazinone ring hampering effective alignment of the molecule in the active site. Subsequent PBP binding experiments confirmed that this class of compound does not bind to PBPs.

Large ring 1,3-bridged 2-azetidinones: Experimental and theoretical studies

“…The IR spectra showed very similar values of carbonyl stretching frequencies for monocyclic (10) and bicyclic compounds (11 and 12). The b-lactam protons H3 and H4 also displayed the same pattern for the three compounds 10-12, but differences arose for H5 proton of the 1-hydroxyethyl side-chain between monocyclic (10) and bicyclic b-lactams (11,12). However, the two bicyclic derivatives are quite similar considering the dihedral angle H4-C4-C5-H5 (see J values).…”

“…In the field of antibiotics, [2] a lot of works has been devoted to the search of more strained, fused bicyclic b- [10,11] and g- [12,13] lactam systems.…”

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

“…the need of a carboxylic function on the substrate/inhibitor for promoting a good interaction with PBP enzymes. Yet, the most stimulating biochemical result was the discovery of novel inhibitors of PBP 2a featuring non-traditional structures: their activities are moderate (10) to modest (11) and weak (12), but well measurable.…”

Study on the Molecular Recognition of Adrenaline by Supramolecular Complexation with Formamide

“…For examples, the H-bonds among peptide bonds in proteins are the key driving forces for forming the organized -helix and -sheet secondary structures. The linkage also plays important roles in the pharmacophores of the antibacterial agents such as penicillins and carbacephems and has been utilized in designing enzyme inhibitors [1]- [4]. Formamide (FA) is one of the simplest molecules usually chosen as a model for studying biological systems exhibiting the peptide type of bonding and DNA structures.…”