Synthesis and structure-activity relationships of inhibitors of bacterial hyaluronidase: An approach to obtain compounds with drug-like properties

摘要: Hyaluronidases are enzymes that predominantly degrade hyaluronan, a major constituent of the extracellular matrix. They can be ubiquitously found throughout animal kingdom and have been isolated from large number different organs venoms. Additionally, hyaluronidases produced by bacteria fungi. In case pathogenic venoms, act as spreading factors. cause local tissue damage to facilitate diffusion pathogens toxins, respectively. Inhibitors required pharmacological tools further investigate their physiological pathophysiological roles these enzymes. Previously, we identified hyaluronidase inhibitors among lipophilic vitamin C, indole, benzoxazole derivatives. Due lack drug-like properties high plasma protein binding, such substances considered inappropriate for in vivo studies. The goal this thesis was design, synthesis, identification, characterization novel low-molecular weight bacterial SagHyal4755 with improved properties. In first attempt, several commercially available drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), were investigated inhibitory activity on hyaluronate lyase bovine testis (BTH). All tested inactive or only weakly active BTH, suggesting inactivity compounds at corresponding human enzyme, PH 20 hyaluronidase. contrast mammalian inhibited compounds. salicylate diflunisal (IC50 (SagHyal4755) = 195 µM) putative lead compound design synthesis chemically related properties. The scaffold modified introduction variously substituted aryl rings via Suzuki-Miyaura coupling led potent inhibitors, example 1,1’:3’,1’’-terphenyl-4-carboxylic acid 4-hydroxy-1,1’:4’,1’’-terphenyl-3-carboxylic which revealed IC50 values about 30 µM 6-fold increased potency compared diflunisal. However, second hyaluronidase, SpnHyl, not analogs, indicating differences between binding pockets In synthetic approach, analogs 6,7-dichloro-1H-indoles 5-hydroxy-1H-indoles synthesized. Whereas showed weak no inhibition both testicular (BTH) two-digit micromolar range determined SagHyal4755. 6,7 Dichloro-1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylic most inhibitor series 16 µM). In general, both, diflunisal- indole-type is strongly dependent presence negatively charged carboxylic group chloro substituents well overall lipophilicity combination structural features resulted lower range. search bioisosteric replacements indole scaffold, small eight 2 phenylindolizine derivatives, without moieties, Except 4-(6-cyanoindolizin-2-yl)benzoic 56 µM), very streptococcal synthesized devoid BTH. A subproject focused upon venoms two snake species, Bitis arietans (viper) Naja siamensis (cobra), regard activity. Both contain molecular 45 kDa 65 kDa, maximum acidic pH (pH 4-7). investigation four selected venom inhibition. Since pure reptile more detailed investigations, cannot ruled out. content raw has taken into account well. This assumption supported compounds, an HPLC based method. Taken together, derived three scaffolds SagHyal4755, but (BTH), hyaluronidases.