Synthesis of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazines that have antibacterial activity and also inhibit inorganic pyrophosphatase

Abstract

Inorganic pyrophosphatases are potential targets for the development of novel antibacterial agents. A pyrophosphatase-coupled high-throughput screening assay intended to detect o-succinyl benzoic acid coenzyme A (OSB CoA) inhibitors led to the unexpected discovery of a new series of novel inorganic pyrophosphatase inhibitors. Lead optimization studies resulted in a series of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazine derivatives that were prepared by an efficient synthetic pathway. One of the tetracyclic triazine analogues 22h displayed promising antibiotic activity against a wide variety of drug-resistant Staphylococcus aureus strains, as well as activity vs. Mycobacterium tuberculosis and Bacillus anthracis, at a concentration that was not cytotoxic to mammalian cells.

Structural and computational dissection of the catalytic mechanism of the inorganic pyrophosphatase from Mycobacterium tuberculosis

“…Low-lM diphosphonate inhibitors selective for mammalian inorganic pyrophosphatases have been reported (Smirnova et al, 1988). A recent HTS campaign yielded the first non-ionic inhibitory compounds with IC 50 $ 30 lM (Lv et al, 2014). Through a deeper understanding of the catalytic mechanism, the unique features of Mtb PPiase, such as the disposition of the active site Asp residues and the two His residues discussed above, may be used as specificity determinants in future development of selective inhibitory compounds against this enzyme.…”

“…coli (Chen et al, 1990), Mycobacterium tuberculosis (Mtb) (Griffin et al, 2011) as well as S. cerevisiae (Lundin et al, 1991) contain family I PPiases, and these enzymes are essential for survival of these organisms. Because of the global clinical significance of Mtb as a deadly pathogen, Mtb PPiase is considered to be a potential target for novel anti-tuberculosis drugs (Biswas et al, 2013;Lv et al, 2014). In addition to extensive structural and biochemical studies on E. coli and S. cerevisiae PPiases Heikinheimo et al, 2000;Merckel et al, 2001;Pohjanjoki et al, 2001;Samygina et al, 2007), X-ray crystallographic studies were also carried out with the Mtb PPiase (Benini and Wilson, 2011;Tammenkoski et al, 2005), providing structural information on the location of a sole phosphate ion in the active site (PDB ID: 1WCF).…”

Synthesis, Characterization, and Antimicrobial Studies of Novel Series of 2,4-Bis(hydrazino)-6-substituted-1,3,5-triazine and Their Schiff Base Derivatives

“…On the other hand, the growing interest in s-triazine derivatives specially its chlorinated derivative (cyanuric chloride) and its efficient reaction with hydrazine to render mono-, di-, or tri-substituted hydrazino derivatives has increased [20][21][22]. Several prepared and well explored hydrazino-s-triazine derivatives were reported and considered with special interest in coordination chemistry and supramolecular chemistry [23,24] as well as their enormous potential in the field of material chemistry [25,26], complexation with large metal ions [27][28][29][30][31][32][33][34][35][36], and pharmaceutical industry [37][38][39][40][41][42][43]. 2…”

Crystallographic and Modeling Study of the Human PPA1 (Inorganic Pyrophosphatase 1): a Potential Anti-cancer Drug Target

“…Efforts had been made to target PPases from pathogenic organisms for small-molecule drug development. Anti-PPase small molecules were shown to have promising antibiotic activity against drug resistant strains of Staphylococcus aureus [34]. Small molecule inhibitors of the VSP1 (vacuolar soluble pyrophosphatase 1) protein from Trypanosoma brucei, the causative agent of African trypanosomiasis (HAT), provided a 40% protection from death in a mouse model of T. brucei infection [35].…”