Discovery of 4,6‐bis(2‐((<i>E</i>)‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity

Russell, Cecilia C.; Stevens, Andrew; Young, Kelly A.; Baker, Jennifer R.; McCluskey, Siobhann N.; Khazandi, Manouchehr; Pi, Hongfei; Ogunniyi, Abiodun D.; Page, Stephen W.; Trott, Darren J.; McCluskey, Adam

doi:10.1002/open.201800241

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…As part of a series of studies we have developed a number of classes of biologically active molecules [ 15 , 16 , 17 , 18 , 19 , 20 ]. With our in-house compound library, we sought to examine one of our compound series, that were originally designed to target the aryl hydrocarbon receptor (AhR) ( Figure 1 ) [ 15 , 21 , 22 , 23 ], for activity against methicillin-resistant Staphylococcus aureus (MRSA), E. coli , Klebsiella pneumoniae , Acinetobacter baumannii and Pseudomonas aeruginosa ; and the yeasts Candida albicans and Cryptococcus neoformans .…”

Section: Introductionmentioning

confidence: 99%

Amino Alcohols as Potential Antibiotic and Antifungal Leads

et al. 2022

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Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.

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Section: Introductionmentioning

confidence: 99%

Amino Alcohols as Potential Antibiotic and Antifungal Leads

et al. 2022

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“…Among the derivatives, monomeric analogues NCL259 and NCL265 showed the best activity against Gram-negative strains in initial screening tests. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) testing showed that concentrations ranging from 8–16 µg/mL inhibited the growth/killed E. coli -type strains ATCC 11229 and ATCC 25922 [ 28 , 29 ]. Additionally, these two compounds demonstrated excellent bactericidal activity against E. coli in kill kinetics experiments, achieving 100% reduction of colony forming units within 20 min at the MIC for E. coli ATCC 25922.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens

Venter

Russell

et al. 2022

Antibiotics

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Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.

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“…Recently, work by Trott and McClusky − has further explored the aminoguanidine chemotype of robenidine, applying a medicinal chemistry approach to repurpose the drug for various bacterial pathogens. Their ongoing research has demonstrated that this chemical scaffold is amenable to synthetic modification and can successfully be refined for activity against pathogens other than Eimeria .…”

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confidence: 99%

Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum

Krollenbrock

Kelly

et al. 2021

ACS Infect. Dis.

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Robenidine is a veterinary drug used in the poultry industry to treat coccidiosis caused by parasites in the Eimeria genus. Though this compound and related aminoguanidines have recently been studied in other pathogens, the chemotype has not been systematically explored to optimize antimalarial activity despite the close genetic relationship between Eimeria and Plasmodium (both are members of the Apicomplexa phylum of unicellular, spore-forming parasites). In this study, a series of aminoguanidine robenidine analogues was prepared and tested in vitro against Plasmodium falciparum , including multidrug-resistant strains. Selected compounds were further evaluated in vivo against murine Plasmodium yoelii in mice. Iterative structure–activity relationship studies led to the discovery of 1 , an aminoguanidine with excellent activity against drug-resistant malaria in vitro and impressive in vivo efficacy with an ED 50 value of 0.25 mg/kg/day in a standard 4-day test.

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Discovery of 4,6‐bis(2‐((E)‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity

Cited by 5 publications

References 28 publications

Amino Alcohols as Potential Antibiotic and Antifungal Leads

Amino Alcohols as Potential Antibiotic and Antifungal Leads

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens

Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum

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