Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent

Autor: Lluís Ballell-Pages, Katja Laqua, Henok Asfaw, Anna Maria Walkowska, Juan Carlos Cuevas-Zurita, Maria Santos Martinez-Martinez, Fraser Cunningham, Peter Imming
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Bacterial Diseases
Physiology
Antitubercular Agents
lcsh:Medicine
Antimycobacterial
01 natural sciences
Chemical synthesis
Mice
Drug Metabolism
Medicine and Health Sciences
lcsh:Science
ADME
Multidisciplinary
Chemistry
Chemical Synthesis
Hep G2 Cells
Body Fluids
Actinobacteria
Blood
Infectious Diseases
Physical Sciences
Anatomy
Half-Life
Research Article
Biosynthetic Techniques
medicine.drug_class
Cell Survival
Materials Science
Material Properties
Microbial Sensitivity Tests
Research and Analysis Methods
Peptides
Cyclic
Blood Plasma
Permeability
03 medical and health sciences
Structure-Activity Relationship
Pharmacokinetics
Species Specificity
medicine
Structure–activity relationship
Potency
Animals
Humans
Tuberculosis
IC50
Peptide Synthesis
Pharmacology
Bacteria
010405 organic chemistry
lcsh:R
Organisms
Biology and Life Sciences
Mycobacterium tuberculosis
Tropical Diseases
Combinatorial chemistry
0104 chemical sciences
030104 developmental biology
Solubility
Drug Design
lcsh:Q
Drug metabolism
Zdroj: PLoS ONE, Vol 12, Iss 4, p e0176088 (2017)
PLoS ONE
ISSN: 1932-6203
Popis: Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 μM and found to be nontoxic against human HepG2 cells up to 100 μM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 μM) and 13c (0.6 μM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development.
Databáze: OpenAIRE
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