Novel bis-cyclic guanidines as potent membrane-active antibacterial agents with therapeutic potential

Teng, P. K.; Nimmagadda, Alekhya; Su, Ma; Hong, Yuzhu; Shen, Ning; Li, Chunpu; Tsai, Ling-Yu; Cao, Jessica; Li, Qi; Cai, Jianfeng

doi:10.1039/c7cc07285f

Cited by 43 publications

(40 citation statements)

References 38 publications

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“…[15] Synthesis of compound 13 is shown as an example of the typical synthesis process (Scheme 1). Intermediate R4 was obtained from the readily accessible reagent R1 in a straightforward manner with decent yield.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 12 and 13 were also not hemolytic, even at a concentration of 250 μg mL −1 . [15] The selectivity decreased slightly if the benzyl group was replaced with an isobutyl group. Overall, compound 13 has the best SI among all the compounds tested.…”

Section: Resultsmentioning

confidence: 99%

“…The NMR data of compounds 1–5 , 12 , 13 , and 16 are consistent with previously published data. [15] The NMR and HRMS data for other compounds are listed below: Compound 6 : 1 H NMR (500 MHz, CD 3 OD): δ=7.64 (d, J =7.5 Hz, 4H), 7.57 (d, J =7.5 Hz, 4H), 7.18–7.33 (m, 20H), 4.22–4.27 (m, 2H), 4.14 (s, 4H), 3.63 (t, J =9.5 Hz, 2H), 3.51–3.57 (m, 2H), 3.42 (dd, J =9.5, 5.0 Hz, 2H), 3.34 (dd, J =9.0, 5.5 Hz, 2H), 3.09 (dd, J =13.5,4.5 Hz, 2H), 2.85 (dd, J =14.0, 8.5 Hz, 2H), 2.62–2.74 (m, 4H), 1.92–2.06 ppm (m, 4H); 13 C NMR (125 MHz, CD 3 OD):δ =165.1, 158.0, 140.9, 137.2, 136.2, 135.7, 134.3, 129.0 (2C), 128.5 (2C), 128.2 (2C), 128.0 (2C), 126.8, 126.6 (2C), 125.8, 119.8, 58.0, 51.7, 42.3, 37.4, 32.1 (2C), 28.3 ppm; HRMS (ESI) C 54 H 59 N 8 O 2 [ M+H ] + calcd=851.4755; found=851.4742. Compound 7 : 1 H NMR (500 MHz, CD 3 OD): δ=7.53 (s, 4H), 7.31–7.34 (m, 4H), 7.24–7.28 (m, 6H), 4.27–4.32 (m, 2H), 4.13, 4.10 (ABq, J =18.0 Hz, 4H), 3.68 (t, J =9.0 Hz, 2H), 3.41–3.48 (m, 4H), 3.25 (ddd, J =15.0, 9.5, 5.5 Hz, 2H), 3.15 (dd, J =13.5, 5.0 Hz, 2H), 2.89 (dd, J =13.5, 8.0 Hz, 2H), 1.58–1.76 (m, 14H), 1.15–1.32 (m, 12H), 0.90–0.97 ppm (m, 4H); 13C NMR (125 MHz, CD 3 OD): δ=165.1, 158.0, 135.8, 134.3, 128.9 (2C), 128.5 (2C), 126.8, 120.1 (2C), 57.9, 51.8, 47.0, 43.1, 37.6, 37.5, 37.3, 33.6, 33.0, 32.9, 26.3, 26.0, 24.0 ppm; HRMS (ESI) C 48 H 67 N 8 O 2 [ M+H ] + calcd=787.5381; found=787.5374. Compound 8 : 1 H NMR (500 MHz, CD 3 OD): δ=8.04 (s, 1H), 7.31–7.34 (m, 4H), 7.24–7.28 (m, 9H), 4.26–4.32 (m, 2H), 4.14, 4.10 (ABq, J =18.0 Hz, 4H), 3.68 (t, J =9.5 Hz, 2H), 3.41–3.47 (m, 4H), 3.25 (ddd, J =14.5, 9.0, 5.5 Hz, 2H), 3.15 (dd, J =13.5, 5.0 Hz, 2H), 2.89 (dd, J =13.5, 8.0 Hz, 2H), 1.60–1.75 (m, 14H), 1.14–1.32 (m, 12H), 0.90–0.96 ppm (m, 4H); 13C NMR (125 MHz, CD 3 OD): δ=165.2, 158.0, 138.6, 135.8, 128.9 (2C), 128.5 (2C), 126.8, 120.1 115.3, 58.0, 51.7, 47.0, 43.1, 37.6, 37.3, 33.7, 33.0, 32.9, 26.3, 26.0 (2C), 24.0 ppm; HRMS (ESI) C 48 H 67 N 8 O 2 [ M+H ] + calcd=787.5381; found=787.5357. Compound 9 : 1 H NMR (500 MHz, CD 3 OD): δ=7.31–7.34 (m, 4H), 7.25–7.27 (m, 6H), 4.24–4.30 (m, 2H), 3.93, 3.89 (ABq, J =17.5 Hz, 4H), 3.60 (t, J =9.5 Hz, 2H), 3.42 (ddd, J =14.5, 9.0, 6.0 Hz, 2H), 3.33 (dd, J =9.5, 6.0 Hz, 2H), 3.21–3.26 (m, 2H), 3.19 (t, J =7.0 Hz, 4H), 3.13 (dd, J =13.5, 5.0 Hz, 2H), 2.85 (dd, J =13.5, 8.0 Hz, 2H), 1.65–1.74 (m, 12H), 1.58–1.62 (m, 2H), 1.50 (p, J =6.5 Hz, 4H), 1.32–1.35 (m, 4H), 1.14–1.31 (m, 12H), 0.85–0.95 ppm (m, 4H); 13C NMR (125 MHz, CD 3 OD): δ=166.9, 158.0, 135.8, 128.9 (2C), 128.5 (2C), 126.8, 57.9, 51.6, 46.6, 43.1, 39.1, 37.5, 37.3, 33.7, 33.0, 32.9, 28.8, 26.3, 26.1, 26.0 (2C), 24.0 ppm; HRMS (ESI) C 48 H 74 N 8 O 2 [ M+H ] + calcd=795.6006; found=795.5998. Compound 10 : 1 H NMR (500 MHz, CD 3 OD): δ=7.30–7.34 (m, 4H), 7.24–7.26 (m, 6H), 4.24–4.30 (m, 2H), 3.94, 3.90 (ABq, J =18.0 Hz, 4H), 3.59 (t, J =9.5 Hz, 2H), 3.45 (ddd, J =15.0, 9.0, 6.5 Hz, 2H), 3.34 (dd, J =9.5, 6.0 Hz, 2H), 3.23–3.29 (m, 2H), 3.19–3.23 (m, 4H), 3.13 (dd, J =13.5, 5.0 Hz, 2H), 2.87 (dd, J =14.0, 8.0 Hz, 2H), 1.51–1.54 (m, 4H), 1.28–1.36 (m, 12H), 0.92 ppm (t, J =6.5 Hz, 6H); 13 C NMR (125 MHz, CD 3 OD): δ=167.0, 157.9, 135.8, 129.0 (2C), 128.5 (2C), 126.8, 57.9, 51.6, 46.7, 42.9, 38.7, 37.5, 31.1, 26.6, 26.2, 25.8, 22.1, 12.9 ppm; HRMS (ESI) C 40 H 63 N 8 O 2 [ M+H ] + calcd=687.5068; found=687.5056. Compound 11 : 1 H NMR (500 MHz, CD 3 OD): δ=7.31–7.34 (m, 4H), 7.24–7.27 (m, 6H), 4.24–4.30 (m, 2H), 3.94, 3.90 (ABq, J =18.0 Hz, 4H), 3.59 (t, J =9.0 Hz, 2H), 3.45 (ddd, J =15.0, 9.0, 6.5 Hz, 2H), 3.34 (dd, J =9.5, 5.5 Hz, 2H), 3.25 (ddd, J =15.0, 9.0, 5.5 Hz, 2H), 3.18 (t, J =7.0 Hz, 4H), 3.14 (dd, J =13.5, 5.0 Hz, 2H), 2.86 (dd, J =13.5, 8.0 Hz, 2H), 1.54–1.69 (m, 4H),1.50 (t, J =6.0 Hz, 4H), 1.30–1.36 (m, 20H), 0.92 ppm (t, J =7.0 Hz, 6H); 13 C NMR (125 MHz, CD 3 OD): δ=166.9, 157.9, 135.8, 128.9 (2C), 128.5 (2C), 126.8, 57.9, 51.5, 46.7, 42.8, 39.2, 37.5, 31.2, 28.9, 26.6, 26.5, ...…”

Section: Methodsmentioning

confidence: 99%

“…[14] These types of compounds display antimicrobial activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis , and vancomycin-resistant Enterococci faecalis, and relatively weaker activity against Gram-negative organisms such as Klebsiella pneumoniae and Pseudomonas aeruginosa . [15] …”

Section: Introductionmentioning

confidence: 99%

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Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

Teng

Peng

et al. 2018

ChemMedChem

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Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a set of bis-cyclic guanidine compounds that show potent antibacterial activity against C. difficile with decent selectivity. Eight compounds showed high in vitro potency against C. difficile UK6 with MIC values of 1.0 μg mL−1, and cytotoxic selectivity index (SI) values up to 37. Moreover, the most selective compound is also effective in the treatment of C. difficile-induced disease in a mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

Teng

Peng

et al. 2018

ChemMedChem

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“…Most of them are peptidomimetics but also polymers or oligomers (molecular weight > 1000 Da) [ 19 , 20 ]. With the aim of overcoming the problems associated with the large size of these molecules, more manageable downsized compounds (molecular weight < 1000 Da) have been also synthesized [ 21 , 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents

et al. 2018

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Cationic and non-peptide small molecules containing a total of six positive charges arranged on one side and a long aliphatic tail on the other have been synthesized and tested against Gram-positive and Gram-negative bacteria. The positive charges have been contributed by two aminophenol residues. These molecules have showed remarkable antimicrobial activity against Gram-positive bacteria including multidrug-resistant strains. Our structure–activity relationship studies demonstrated the importance of the length and flexibility of the hydrophobic tail for the antimicrobial activity. Importantly, these compounds are non-toxic to eukaryotic cells at the concentration affecting growth in bacteria, reflecting an acceptable margin of safety. The small size and easy synthetic accessibility of our molecules can be of interest for the further development of novel antimicrobials against Gram-positive bacterial pathogens, including multidrug-resistant strains.

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Nano‐Sized Lipidated Dendrimers as Potent and Broad‐Spectrum Antibacterial Agents

Gide

Nimmagadda

et al. 2018

Macromol. Rapid Commun.

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There is considerable interest in the development of antimicrobial polymers including dendrimers due to the ease of synthesis and low manufacturing cost compared to host defense peptides (HDPs). Herein, a new class of nanomaterials—lipidated amphiphilic dendrimers—is presented that mimic the antibacterial mechanism of HDPs by compromising bacterial cell membranes. Unlike conventional dendrimers that are prepared generation by generation symmetrically with molecular weight distribution, these lipidated dendrimers are prepared on the solid phase with a hanging lipid tail and precisely controlled structure. It is shown through rational design that these lipidated dendrimers display potent and selective antimicrobial activity against both Gram‐positive and Gram‐negative bacteria, including multidrug‐resistant strains. In addition to antibacterial activity against planktonic bacteria, these dendrimers are also shown to inhibit bacterial biofilms effectively. This class of dendrimers as a new class of biomaterials may lead to a useful generation of antibiotic agents with practical applications.

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Novel bis-cyclic guanidines as potent membrane-active antibacterial agents with therapeutic potential

Cited by 43 publications

References 38 publications

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

A Novel Class of Cationic and Non-Peptidic Small Molecules as Hits for the Development of Antimicrobial Agents

Nano‐Sized Lipidated Dendrimers as Potent and Broad‐Spectrum Antibacterial Agents

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