A new approach towards peptidosulfonamides: synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymes MurD and MurE

Structural and Functional Characterization of Enantiomeric Glutamic Acid Derivatives as Potential Transition State Analogue Inhibitors of MurD Ligase

“…Its high (stereo)specificity for D-glutamic acid has been shown by studying structurally related analogues tested as substrates or inhibitors. 21,22 There have been several successful attempts to identify MurD inhibitors by using the transition-state hypothesis [23][24][25][26][27][28][29] and it was suggested that D-glutamic acid represents an essential fragment of a potent inhibitor. 25,26 Based on this rationale we recently synthesized a series of sulfonamide derivatives of D-glutamic acid, as analogues of the tetrahedral intermediate (unpublished results).…”

Multi-targeted therapy for leprosy: Insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy

“…Among these, transition-state analogs like phosphonates, phosphinates and sulfonamides have been described as inhibitors of MurC Reck et al, 2001), MurD (Tanner et al, 1996;Gegnas et al, 1998;Strancar et al, 2006;Kotnik et al, 2007b;Humljan et al, 2006Humljan et al, , 2008, MurE (Strancar et al, 2007;Fig. 5.…”

Phosphinate Inhibitors of UDP‐N‐Acetylmuramoyl‐L‐Alanyl‐D‐Glutamate: L‐Lysine Ligase (MurE)

“…It is thus reasonable to evaluate their inhibition of MurE, for which they could act as substrate analogues [12]. This was the case for the b-sulfonamidopeptides, which were moderate inhibitors of MurE from S. aureus [11]. Here, we report on the inhibitory potencies of the phosphinate compounds on MurE from S. aureus, which represents one of the major pathogenic species.…”

“…Lately, we reported on the synthesis and structureactivity relationships of two types of transition-state analogue inhibitors of MurD: i) a series of phosphinate compounds of general formula R-(L,D)-Ala-W(PO 2 -CH 2 )-(L,D)-Glu were shown to be good inhibitors of the E. coli enzyme [9,10]; ii) in contrast, a series of b-sulfonamidopeptides of general formula R-L-Ala-W(CH 2 -SO 2 -NH)-D-Glu were very poor MurD inhibitors [11]. As MurE follows MurD in the cascade of biosynthetic amino acid addition, the transition-state analogue inhibitors of MurD show structural resemblance to the substrate for MurE (Scheme 1).…”