Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action

Bongard, Jens; Schmitz, Anna Laura; Wolf, Alex; Zischinsky, Gunther; Pieren, Michel; Schellhorn, Birgit; Bravo-Rodríguez, Kenny; Schillinger, Jasmin; Koch, Uwe; Nußbaumer, Peter; Klebl, Bert; Steinmann, Jörg; Buer, Jan; Sánchez-García, Elsa; Ehrmann, Michael; Kaiser, Markus

doi:10.1002/cmdc.201900193

Cited by 13 publications

(14 citation statements)

References 29 publications

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“…In this case, the amination/cyclization process is promoted by the couple HgCl 2 /TFA and DMF as solvent. Chu et al and Kaiser et al further reported a multistep synthesis of pyrazolo[1,5- a ][1,3,5]triazine-2,4-diamine derivatives as potent protein kinase CK2 inhibitors and antibiotics (Scheme , c) . Although the above contributions we discuss here are useful for the construction of pyrazolo[1,5- a ][1,3,5]triazines, , these reactions proceed under the conditions of high reaction temperature, microwave irradiation, and multistep reactions.…”

Section: Introductionmentioning

confidence: 93%

Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines

et al. 2021

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A new photocatalyst-free visible-light-enhanced strategy for the synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines via the formation of electron donor–acceptor (EDA) complexes is reported. The in situ generated pyrazolthiourea intermediates from 1H-pyrazol-3-amines and isothiocyanates undergo formal [4 + 2] annulation with 1,1,3,3-tetramethylguanidines (TMG) to deliver the corresponding products involved in three C–N bond formations in a one-pot protocol. The formation of EDA complex from pyrazolthiourea and TMG is confirmed by UV–vis spectroscopy and 1H NMR experiments. Moreover, this mild reaction proceeds in the absence of any external transition metals, oxidants, bases, and ligands. This efficient methodology for the synthesis of purine analogues pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines provides potential synthetic applications in the field of drug research and development.

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Section: Introductionmentioning

confidence: 93%

Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines

et al. 2021

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“…7 A). Bongard et al reported that modified pyrazolo[1,5- a ]-1,3,5-triazines were potential E. coli DegS inhibitors [19] . They demonstrated these compounds could repress the outer membrane stress response and act synergistically with antibiotics in E. coli ( Fig.…”

Section: Drug Development Targeting Htra Proteinsmentioning

confidence: 99%

“…Certain HtrA proteins can be secreted from the cell to facilitate bacterial invasion [18] . Their significant physiological functions, particularly those in virulence and antibiotic resistance, suggests that members of the HtrA family constitute attractive drug targets [10] , [19] , [20] , [21] , [22] .…”

Section: Introductionmentioning

confidence: 99%

Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view

Song

Kang

et al. 2022

Computational and Structural Biotechnology Journal

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Members of the high temperature requirement A (HtrA) protein family are widely distributed amongst prokaryotic and eukaryotic species. HtrA proteins have ATP-independent dual chaperone-protease activity and mediate protein quality control. Emerging evidence indicates that HtrA family members are vital for establishing infections and bacterial survival under stress conditions. Bacterial HtrA proteins are increasingly thought of as important new targets for antibacterial drug development. Recent literature suggests that HtrA protein AlgW from Pseudomonas aeruginosa has distinct structural, functional, and regulatory characteristics. The novel dual-signal activation mechanism seen in AlgW is required to modulate stress and drug responses in bacteria, prompting us to review our understanding of the many HtrA proteins found in microorganisms. Here, we describe the distribution of HtrA gene orthologues in pathogenic bacteria, discuss their structure–function relationships, outline the molecular mechanisms exhibited by different bacterial HtrA proteins in bacteria under selective pressure, and review the significance of recently developed small molecule inhibitors targeting HtrA in pathogenic bacteria.

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“…The pyrazolo [1,5-a] [1,3,5]triazine is a heterocyclic system which has generated considerable interest in the communities of academic and industrial medicinal chemists [1,2]. This nitrogen-rich heterocyclic core was intensively developed as a bioisosteric substitute of biogenic purines (e.g., adenine, guanine, and xanthine in Figure 1) for the conception of potentially bioactive compounds in a wide range of biological applications [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In this context, numerous synthetic routes of various substituted pyrazolo [1,5-a] [1,3,5]triazines have been yet reported [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines

2021

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This paper reports a convenient sequential one-pot approach for the synthesis of an array of 14 pyrazolo[1,5-a][1,3,5]triazines, substituted in C8 by halogen (Br), various functions (CN and CO2Et) and alkyl or (het)aryl groups. This study confirms the interest of combining the efficient heating obtained under dielectric microwave heating and the achievement of sequential one-pot reactions, avoiding the tedious work-up and purification of intermediate compounds, achieving sustainable synthesis processes. Considering usual conventional methods, this microwave protocol is featured by advantages in terms of yields, reaction times, and convenient gram scale synthesis.

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Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action

Cited by 13 publications

References 29 publications

Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines

Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines

Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view

Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines

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