- Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens
-
Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, including polymyxin- and carbapenem-resistant strains.
- Wesseling, Charlotte M. J.,Slingerland, Cornelis J.,Veraar, Shanice,Lok, Samantha,Martin, Nathaniel I.
-
p. 3314 - 3335
(2021/11/24)
-
- Discovery of decamidine as a new and potent PRMT1 inhibitor
-
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (2j), which possesses the longest linker in the series, displayed 2- and 4-fold increase in PRMT1 inhibition (IC50 = 13 μM), compared with furamidine and stilbamidine. The inhibitory activity toward PRMT1 was validated by secondary orthogonal assays. Docking studies showed that the increased activity is due to the extra interaction of the amidine group with the SAM binding pocket, which is absent when the linker is not long enough. These results provide structural insights into developing the amidine type of PRMT1 inhibitors.
- Zhang, Jing,Qian, Kun,Yan, Chunli,He, Maomao,Jassim, Brenson A.,Ivanov, Ivaylo,Zheng, Yujun George
-
p. 440 - 444
(2017/03/08)
-
- Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia
-
A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.
- Tidwell,Jones,Geratz,Ohemeng,Cory,Hall
-
p. 1252 - 1257
(2007/10/02)
-
