Synthesis and SAR of phenylazoles, active against Staphylococcus aureus Newman

Solomin, Vitalii V.; Fernandez-Ciruelos, Blanca; Velikova, Nadya; Wells, Jerry M.; Albanese, Mark J.; Adhav, Anmol; Jirgensons, Aigars

doi:10.1007/s10593-023-03151-9

Cited by 5 publications

(5 citation statements)

References 18 publications

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“…Details of the synthesis of the compounds can be found in Solomin et al . (30); the schematic synthesis of DPP-22 is shown in Supplementary Figure 4 (Figure SF4). Chemical compounds DPP-1 , 3 , 5 , 7 , 10 , 12 , 14 , 15 , 16 , 27 , 28 , 19 and 20 were purchased from MolPort (Riga, Latvia).…”

Section: Methodsmentioning

confidence: 99%

“…The chemical compounds DPP-2, 4, 6, 8, 9, 11, 13, 21, 22, 23 and 24 were synthesized by the Latvian Institute of Organic Synthesis. Details of the synthesis of the compounds can be found in Solomin et al (30); the schematic synthesis of DPP-22 is shown in Supplementary Figure 4 (Figure SF4). Chemical compounds DPP-1, 3, 5, 7, 10, 12, 14, 15, 16, 27, 28, 19 and 20 were purchased from MolPort (Riga, Latvia).…”

Section: Chemical Compoundsmentioning

confidence: 99%

“…A collection of 24 DPP analogues was synthesized (30) or purchased to further expand the SAR around the diphenylpyrazole scaffold (Table 1). These analogues were first tested for minimal inhibitory concentration (MIC) against the Gram-positive S. aureus.…”

Section: Structure-activity Relationship (Sar) Of Antimicrobial 34-di...mentioning

confidence: 99%

“…Compound substitutions (R1 to R5 and X) from the A, B or C rings of the scaffold as indicated in the diagram are also depicted. * 1-OH is absent ** C-ring is absent † Data previously published in Solomin et al(30).…”

mentioning

confidence: 93%

“…In a previous study, we have reported synthetic derivatives featuring a 3,4-diphenylpyrazole core with antibacterial activity against S. aureus (30). Herein, we investigate the antibacterial activity and potential inhibition of HKs for a subset of these derivatives and related compounds from commercial vendors as well as the mechanisms responsible for their antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing Hsp90 inhibitors as antimicrobials targeting two-component systems identifies compounds leading to loss of bacterial membrane integrity

Fernandez-Ciruelos,

Albanese,

Adhav

et al. 2023

Preprint

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The discovery of antimicrobials with novel mechanisms of action is crucial to tackle the foreseen global health crisis due to antimicrobial resistance. Bacterial two-component signalling systems (TCS) are attractive targets for the discovery of novel antibacterial agents. TCS-encoding genes are found in all bacterial genomes and typically consist of a sensor histidine kinase (HK) and a response regulator (RR). Due to the conserved Bergerat fold in the ATP-binding domain of the TCS HK and the human chaperone Hsp90, there has been much interest in repurposing inhibitors of Hsp90 as antibacterial compounds. In this study, we explore the chemical space of the known Hsp90 inhibitor scaffold 3,4-diphenylpyrazole (DPP), building on previous literature to further understand their potential for HK inhibition. Six DPP analogues inhibited HK autophosphorylationin vitroand had good antimicrobial activity against Gram-positive bacteria. However, mechanistic studies showed that their antimicrobial activity was related to damage of bacterial membranes. In addition, DPP analogues were cytotoxic to mammalian cancer cell lines and induced the cell arrest phenotype shown for other Hsp90 inhibitors. We conclude that these DPP structures can be further optimized as specific disruptors of bacterial membranes providing binding to Hsp90 and cytotoxicity are lowered. With respect to the original hypothesis, the X-ray crystal structure of resorcinol, a substructure of the DPP derivatives, bound to the HK CheA represents a promising starting point for the fragment-based design of novel HK inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Chemical Compoundsmentioning

confidence: 99%

Section: Structure-activity Relationship (Sar) Of Antimicrobial 34-di...mentioning

confidence: 99%

mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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