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Synthesis of Important Chiral Building Blocks for Pharmaceuticals Using Lactobacillus and Rhodococcus Alcohol Dehydrogenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marion Rauter, Simon Krebs, Gotthard Kunze
The separation of both enantiomers from a racemic mixture by chiral chromatography or chiral resolution as required after chemical synthesis is cumbersome and costly. Maximum yield is low with about 50% with regard to substrate concentration. Although optically active catalysts such as 2,2′–bis(diphenylphosphino)–1,1′–binaphthyl (BINAP) are available, they are expensive and require the use of physiologically problematic noble or transition metals (Sheldon, 2008).
Current Inhibitors of Dengue Virus
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
J. Jonathan Harburn, G. Stuart Cockerill
The Novartis Institute for tropical disease has contributed a number of chemotypes to the investigation of inhibition of the DENV polymerase. The spiro-pyrazolopyridinones are our first example of this effort (Wang et al. 2015). This class of compound was discovered by a phenotypic screen of the Novartis library; specifically, the utilisation of a DENV2 sub-genomic replicon in A549 cells. Following an HCV replicon exclusion assay, hit compounds were evaluated in whole virus assays against all four serotypes and a representative group of other viruses (Figure 6). The spiro-pyrazolopyridinone 6-1 was identified from this screen and chiral resolution by chiral HPLC identified R stereoisomer as the active enantiomer with an approximate 200 fold differential over its S form. Lead optimisation identified the pyridyl variant 6-2 (Zou et al. 2015). This compound was sufficiently potent against DENV2 with improved solubility (504 μM) and bioavailability (63%) in rats, albeit with a somewhat compromised microsomal stability. Compound 6-2 was progressed into a mouse model of DENV2 viremia. The compound was dosed either once daily (QD at 100 mg/kg) or twice daily (BID at 50 mg/kg) and a 1.9 log reduction in viral titre could be observed relative to the control group.
Stereoselective pharmacokinetics and tissue distribution of levodropropizine after administration of pure levodropropizine and the rac-dropropizine to Sprague–Dawley rats
Published in Xenobiotica, 2020
Bhavesh Babulal Gabani, Umesh Todmal, Neeraj Kumar Saini, Vinod A. Balakrishna, Suresh P. Sulochana, Ashok Timmapuram, Mohd Zainuddin, Narayanan Balaji, Praharaj Shuvranshu, Nuggehally R. Srinivas, Ramesh Mullangi
The aim of this study was to investigate in a comprehensive manner enantioselective aspects of the pharmacokinetics and tissue distribution of LDP vs. DDP in rats relative to rac-dropropizine following single oral and intravenous doses of both pure LDP and rac-dropropizine. Due to the commercial lack of availability of DDP, a limited quantity of DDP was obtained in the laboratory by chiral resolution of rac-dropropizine to permit pharmacokinetic work related to in vitro metabolism and in vivo chiral inversion of DDP. The employment of a chiral assay permitted the quantitation of LDP and DDP in the plasma/tissue samples and to monitor the chiral inversion, if any following oral and intravenous administration of rac-dropropizine and LDP/DDP to rats.
Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Giulia Rotondi, Paolo Guglielmi, Simone Carradori, Daniela Secci, Celeste De Monte, Barbara De Filippis, Cristina Maccallini, Rosa Amoroso, Roberto Cirilli, Atilla Akdemir, Andrea Angeli, Claudiu T. Supuran
The chiral resolution of the single sulfoxide enantiomers did not give a specific trend, with few enantiomers exhibiting better activity compared with the related optical isomer. The benzyl moiety was essential for the inhibition and the presence of halogen on the ring improved activity when compared with the unsubstituted analogues. The replacement of phenyl ring with linear alkyl chains impaired the activity, while raising the selectivity. The benzoyl moiety was not tolerated by this scaffold, affording compounds ineffective against all the tested isoforms. These outcomes could be related to the loss of hydrophobic interactions due to the phenyl ring shift, clashes with amino acids owing to the ring new position, or both of them. Nevertheless, the reasons of these data might be other. In fact, the inserted “spacer” (the carbonyl group), has an own steric hindrance along with specific bond angles and a stable dipole; all these features could affect negatively the interaction with the isoform IX. Finally, the substitution of the sulphur atom with oxygen, nitrogen one, or methylene underlined the importance of the sulphur atom for the activity of these compounds, because all the obtained derivatives were inactive against all the tested isoforms. Furthermore, some selected compounds were also tested against hCA XII to preliminary provide information on this target. All the derivatives, except compounds 16 and 18, were inactive. Sulphone 18 was a potent and selective hCA XII inhibitor with Ki 0.066 µM, whereas sulphur-based 16 was a medium-potency inhibitor.
A 2018–2019 patent review of metallo beta-lactamase inhibitors
Published in Expert Opinion on Therapeutic Patents, 2020
Nakita Reddy, Mbongeni Shungube, Per I Arvidsson, Sooraj Baijnath, Hendrik G Kruger, Thavendran Govender, Tricia Naicker
Further investigation of the DBO derivatives by Barbion et al. [51] afforded 44 other compounds, with only four (compounds 12–15, Figure 4) showing activity against different MBLs (IMP8, VIM-1, and VIM-4). These compounds included compound 12 in its enantiomerically pure form, i.e. compound 13, that was obtained via preparative chiral resolution of a synthetic intermediate. This activity was demonstrated alone (MIC: 0.5–4 mg/L) as well as synergistically (MIC: ≤ 0.125–0.25 mg/L), when administered with 4 mg/L of ceftazidime.