Design, synthesis and structure–activity relationships of substituted oxazole–benzamide antibacterial inhibitors of FtsZ

Stokes, Neil R.; Baker, Nicola; Bennett, James M.; Chauhan, Pramod K.; Collins, Ian; Davies, David T.; Gavade, Maruti; Kumar, Dushyant; Lancett, Paul; Macdonald, Rebecca; MacLeod, Leanne; Mahajan, Anu; Mitchell, Jeffrey P.; Nayal, Narendra; Nayal, Yashodanand Nandan; Pitt, Gary R. W.; Singh, Mahipal; Yadav, Anju; Srivastava, A. K.; Czaplewski, Lloyd G.; Haydon, David J.

doi:10.1016/j.bmcl.2013.11.002

Cited by 75 publications

(60 citation statements)

References 11 publications

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“…Solubility issues have been noted with oxazoles and thiazoles, but these heterocycles are commonly used for successful drug discovery work (for an example by Stokes [40]). As part of the qHTS process for this study, it is determined if there are issues with precipitation of materials through visual inspection for clouding of the wells in the sample plates.…”

Section: Resultsmentioning

confidence: 99%

“…These heterocyclic rings increase the rigidity of the molecule and may potentially alter binding potency by reducing mobility around the amide group. Incorporating an oxazole heterocycle in bacterial cell division protein FtsZ inhibitors was reported to produce scaffolds with improved pharmacokinetic properties and increased metabolic stability [40]. Furthermore, amide linkages are typically considered biologically labile groups, so alteration at this site may possibly increase metabolic stability toward nonspecific amidases in vivo.…”

Section: Aimmentioning

confidence: 99%

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Oxazole and Thiazole Analogs of Sulindac for Cancer Prevention

et al. 2018

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Aim:Experimental and epidemiological studies and clinical trials suggest that nonsteroidal antiinflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs. Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA. Graphical abstract:

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Section: Resultsmentioning

confidence: 99%

Section: Aimmentioning

confidence: 99%

Oxazole and Thiazole Analogs of Sulindac for Cancer Prevention

et al. 2018

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“…In order to further increase the solubility of compound 18, a prodrug 19 was synthesized. The solubility of 19 was 2-fold higher than its parent compound [94,95] To further increase the pharmacological properties of PC190723, Pilch and coworkers synthesized 1-methylpiperidine-4-carboxamide TXY541 (20, Figure 4), which is a prodrug of PC190723. The compound was effective against MRSA [96].…”

Section: Dichamanetin and Its Derivativementioning

confidence: 99%

“…The C5 position of the oxazole moiety can be modified with alkyl, aryl or halogen substituents to achieve higher potency. In this series of compounds, 5-bromo-and 5-chlorooxazolyl analogs exhibit high activity against a mutant strain of S. aureus, G196A [94,95]. To increase the pharmacokinetic parameters of the compounds, polar groups such as alcohol, amine, carboxylic acid and heterocycles were incorporated to the pseudobenzylic position (−CH(R)−O− moiety).…”

Section: Dichamanetin and Its Derivativementioning

confidence: 99%

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

Sun¹,

Wong²

2018

Fighting Antimicrobial Resistance

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“…Its appeal is further supported for several reasons: (i) it is an essential bacterial protein for survival; (ii) it is highly conserved across many bacterial species, making it a potential broad target; (iii) it is not present in eukaryotes, and toxicity therefore would be expected to be low; and (iv) it is a novel target currently unexploited by other therapeutic options and therefore would be expected to present a low probability of cross-resistance with other therapies. Previous in vitro studies have demonstrated that a number of FtsZ inhibitor compounds contain antibacterial potency against Gram-positive pathogens, including isolates with phenotypic resistance to other antibiotics (14,(45)(46)(47)(48)(49)(50)(51).…”

Section: Figmentioning

confidence: 99%

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

Lepak

Parhi²,

Madison

et al. 2015

Antimicrob Agents Chemother

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Antibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5 Staphylococcus aureus isolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C max ) were relatively linear over the doses studied. Methicillin-resistant Staphylococcal aureus (MRSA) infections are a major public health threat (1). In the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80 thousand illnesses and 11 thousand deaths yearly (2). Ambulatory visits for cases of skin and soft tissue infection (SSTI) continue to increase in number and amounted to more than 14 million in a 2005 survey (3). Methicillin-resistant S. aureus infections account for a disproportionate rise in the incidence of those cases and in the need for hospitalization and unfortunately have limited therapeutic options (3-6). Novel antimicrobial agents that target cellular functions distinctly different from those targeted by current therapies and that show activity against drug-resistant isolates are urgently needed (7-10). Bacterial cell division represents an attractive area for antibiotic research to meet these needs.FtsZ is a major functional protein involved in cell division through formation of a Z-ring polymeric structure of FtsZ subunits (11-13). Disruption of this process leads to inhibition of cell division and eventual cell death (14). In addition to its novel mechanism of action, FtsZ is an attractive drug target because it is highly conserved in bacteria but absent in eukaryotic cells.We describe a pharmacodynamic (PK) evaluation of a methoxybenzamide FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, in a murine neutropenic thigh infection model against S. aureus. The impact of dose and dosing regimen on the in vivo efficacy of this drug was assessed. Specifically, the studies included were designed to (i) determine the pharmacokinetic/ pharmacodynamic (PK/PD) index (peak serum level divided by the MIC [C max /MIC], area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC ratio], or duration of time serum levels exceed the MIC [time above MIC]) associated with optimal drug efficacy and (ii) identify the magnitude of the PK/PD index value required for efficacy among multiple S. aureus isolates, including those with beta-lactam resistance. MATERIALS AND METHODSOrganisms, media, and anti...

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Design, synthesis and structure–activity relationships of substituted oxazole–benzamide antibacterial inhibitors of FtsZ

Cited by 75 publications

References 11 publications

Oxazole and Thiazole Analogs of Sulindac for Cancer Prevention

Oxazole and Thiazole Analogs of Sulindac for Cancer Prevention

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

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