600173-41-9Relevant articles and documents
Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents
Tiwari, Ashutosh Prasad,Sridhar,Boshoff, Helena I.,Arora, Kriti,Gautham Shenoy,Vandana,Varadaraj Bhat
, p. 1265 - 1279 (2019/11/03)
Abstract: Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4–7?μM) and Mycobacterium bovis (% inhibition at 10?μM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development. Graphic abstract: [Figure not available: see fulltext.]
Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains of?Mycobacterium tuberculosis
Kar, Sidhartha S.,Bhat, Varadaraj G.,Shenoy, Vishnu P.,Bairy, Indira,Shenoy, G. Gautham
, p. 60 - 66 (2018/12/05)
In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives (5a–f, 6a–f) were designed and synthesized. The representative compounds showed promising in vitro activity against drug-susceptible, isoniazid-resistant, and multidrug-resistant strains of Mycobacterium tuberculosis with MIC values of 1.56?μg/ml (6b), 6.25?μg/ml (6a–d), and 3.125?μg/ml (6b–c), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC50?>?300?μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug-likeness.
A route to the structure proposed for puetuberosanol and approaches to the natural products marshrin and phebalosin
Gillmore, Adam,Lauret, Christelle,Roberts, Stanley M.
, p. 4363 - 4375 (2007/10/03)
Synthesis of the structure claimed for puetuberosanol 1 (using the Juliá-Colonna oxidation in a key step) showed that the natural product was a different material. The isomeric epoxy alcohols 16-18 can be discounted from the alternatives. An analogue 19 of marshrin 2 was prepared but the synthesis of the natural product was thwarted by failure of a Juliá-Colonna oxidation in the key step. The epoxy ketone 29 was prepared by Darzens condensation and was converted into (±)-phebalosin 3.
