Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents

Abstract

Bicyclic pyrazolidinones are a class of synthetic antibacterial agents in which the beta-lactam ring is replaced by a five-membered ring. These compounds possess electronic and shape properties required for inhibiting penicillin-binding proteins essential for bacterial cell growth. A novel approach called the hypersurface iterative projection (HIP) method, which is based on three-dimensional computer graphics, allows available structure-activity information to be extrapolated to new synthetic targets. By updating the data set as the SAR evolves, the computer graphics reveal regions of parameter space to explore for optimum activity and regions yet unexplored. A large substituent parameter database is used to propose appropriate substituents. For the bicyclic pyrazolidinones, lipophilicity and particularly electron-withdrawing properties of the 3-substituent are shown to correlate strongly with minimum inhibitory concentrations (MIC). Antibacterial potency is intimately related to the activating effect of 3-substituents on chemical reactivity. The HIP method succeeded in proposing the most potent member of the series prior to synthesis and also showed when all of parameter space was reasonably well explored to the extent the chemistry allowed.

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

“…The stability of 1 is a reflection of the mild electron-withdrawing nature of the C(3) amide group, as mentioned earlier. 18 Although highly soluble, 1 has poor Caco-2 permeability and would not be expected to have oral bioavailability. Stability to both human and CD-1 mouse microsomes is notable with a half-life of >60 min in both preparations.…”

“…16,17 Broadly, MIC correlates with the electron withdrawing nature of the σ p value of the C(3) substituent and is tunable for reactivity and stability. 14,18 Here, we use only a mildly electron-withdrawing amide group at C(3), which imparts low reactivity and remarkable stability, while simultaneously using the amide to append a siderophore moiety (Figure 1).…”

Synthesis, crystal structure and Hirshfeld surface analysis of dimethyl 3-(3-bromophenyl)-6-methyl-7-oxo-3,5,6,7-tetrahydropyrazolo[1,2-a]pyrazole-1,2-dicarboxylate

“…Until now, several 1,3-dipoles, such as azomethine ylides (El Ajlaoui et al, 2015), nitrones (Jen et al, 2000;Kano et al, 2005;Suga et al, 2005) and carbonyl ylides (Suga et al, 2007;Nambu et al, 2009;Padwa 2011), have been studied. Among them, N,N 0 -cyclic azomethine imines (Stanovnik et al, 1998;Qiu et al, 2014;Na ´jera et al, 2015;Xu & Doyle, 2014), have been increasingly employed in cycloadditions for the synthesis of pyrazolones and the related dinitrogen-fused heterocyclic derivatives with significant biological activities (Ternansky et al, 1993;Boyd, 1993;Muehlebach, et al, 2009).…”

Hydrogen bond and internal rotations barrier: DFT study on heavier group-14 analogues of formamide

“…Formamide 1 had attracted much interest to characterize its fundamental properties for the last two decades since it is the simplest species containing the amide linkage (–CO–NH–), which is a pharmacophore of the antibacterial agents and designed enzyme inhibitors . Recent reports for organosilicon chemistry showed that silicon substitution can improve bio‐activity of drug derivative by modifying their selectivity, metabolization rate and tissue distribution since silicon slightly differs from carbon in atomic size, electronegativity and lipophilicity .…”