Lipophilic efficient phenylthiazoles with potent undecaprenyl pyrophosphatase inhibitory activity

Elsebaei, Mohamed M.; Mohammad, Haroon; Samir, Amgad; Abutaleb, Nader S.; Norvil, Allison B; Michie, Amie R; Moustafa, Mohamed E.; Samy, Hebatallah; Gowher, Humaira; Seleem, Mohamed N.; Mayhoub, Abdelrahman S.

doi:10.1016/j.ejmech.2019.04.063

Cited by 25 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The UppP activity of compound 16 was investigated utilizing previously described methods . Putative inhibitors for UppP were diluted in DMSO to designated concentrations.…”

Section: Methodsmentioning

confidence: 99%

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus

et al. 2020

Self Cite

View full text Add to dashboard Cite

Exploring the structure–activity relationship (SAR) at the cationic part of arylthiazole antibiotics revealed hydrazine as an active moiety. The main objective of the study is to overcome the inherited toxicity associated with the free hydrazine. A series of hydrocarbon bridges was inserted in between the groups, to separate the two amino groups. Hence, the aminomethylpiperidine-containing analog 16 was identified as a new promising antibacterial agent with efficient antibacterial and pharmacokinetic profiles. Briefly, compound 16 outperformed vancomycin in terms of the antibacterial spectrum against vancomycin-resistant staphylococcal and enterococcal strains with minimum inhibitory concentrations (MICs) ranging from 2 to 4 μg/mL, which is a faster bactericidal mode of action, completely eradicating the high staphylococcal burden within 6–8 h, and it has a unique ability to completely clear intracellular staphylococci. In addition, the initial pharmacokinetic assessment confirmed the high metabolic stability of compound 16 (biological half-life >4 h); it had a good extravascular distribution and maintained a plasma concentration higher than the average MIC value for over 12 h. Moreover, compound 16 significantly reduced MRSA burden in an in vivo MRSA skin infection mouse experiment. These attributes collectively suggest that compound 16 is a good therapeutic candidate for invasive staphylococcal and enterococcal infections. From a mechanistic point of view, compound 16 inhibited undecaprenyl diphosphate phosphatase (UppP) with an IC50 value of 29 μM.

show abstract

“…The UppP activity of compound 16 was investigated utilizing previously described methods . Putative inhibitors for UppP were diluted in DMSO to designated concentrations.…”

Section: Methodsmentioning

confidence: 99%

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many phenylthiazole scaffolds are designed against multidrug-resistant bacteria in addition to their potential anti-MRSA properties. Targeting UppPase, novel phenylthiazoles are prepared alongside accounting for aqueous solubility property [27].…”

Section: Phenylthiazolesmentioning

confidence: 99%

Synthesis, pharmacological evaluation and structure-activity relationship of recently discovered enzyme antagonist azoles

Dorababu¹

2020

Heliyon

View full text Add to dashboard Cite

Global people are suffering from the legion of diseases. Cytotoxic property of the chemical compound would not solely influence effective drug properties and reduce unnecessary side effects. Proteins/enzymes responsible for microbe proliferation or survival are specifically targeted and inhibited successfully making the cells to undergo apoptosis. Furthermore, isoforms of essential enzymes have distinct physiological functions; thereby inhibition of essential enzyme isoforms is an apt way to the clinical approach of disease neutralization. Drugs are designed so as to play significant roles such as signaling pathways in the oncogenic process including cell proliferation, invasion, and angiogenesis. The present review comprises collective information of the recent synthesis of various organic drug compounds in brief, which could inhibit particular enzyme. The review also covers the correlation of the structure of a drug molecule designed and its inhibitory activity. Also, the most significant enzyme inhibitors are highlighted and structural moieties/core units responsible for remarkable inhibitory values are emphasized.

show abstract

“…During the last five years, our group has optimized polysubstituted phenylthiazoles as a new class of antibacterial agents [8][9][10]. Our synthesized compounds were screened intuitively against bacterial and fungal species to assess their antimicrobial activity prior to further investigation.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

et al. 2021

Self Cite

View full text Add to dashboard Cite

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1’-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

show abstract

Lipophilic efficient phenylthiazoles with potent undecaprenyl pyrophosphatase inhibitory activity

Cited by 25 publications

References 36 publications

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus

Synthesis, pharmacological evaluation and structure-activity relationship of recently discovered enzyme antagonist azoles

Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

Contact Info

Product

Resources

About