Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold-A Short Review of Most Recent Studies 2013-2022.

The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013-2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure-Activity-Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.

Biocatalytic asymmetric synthesis of (R)-1-tetralol using Lactobacillus paracasei BD101.

Asymmetric bioreduction of ketones is a fundamental process in the production of organic molecules. Compounds containing tetralone rings are found in the structure of many biologically active and pharmaceutical molecules. Biocatalytic reduction of ketones is one of the most promising and significant routes to prepare optically active alcohols. In this study, the reductive capacity of Lactobacillus paracasei BD101 was investigated as whole-cell biocatalyst in the enantioselective reduction of 1-tetralone (1). In biocatalytic reduction reactions, the conversion of the substrate and the enantiomeric excess (ee) of the product are significantly affected by optimization parameters such as temperature, agitation rate, pH, and incubation time. Effects of these parameters on ee and conversion were investigated comprehensively. (R)-1-tetralol ((R)-2), which can be used to treat disorder such as obsessive compulsive, post-traumatic stress, premenstrual dysphoric, and social anxiety, was manufactured in enantiopure form, high yield and gram-scale, using whole-cell biocatalysts of L. paracasei BD101. The 7.04 g of (R)-2 was obtained in optically pure form with 95% yield. Also, to our knowledge, this is the first report on production of (R)-2 using whole-cell biocatalyst in excellent yield, conversion, enantiopure form and gram scale. This is a clean, eco-friendly and cheap method for the synthesis of (R)-2 compared with chemical catalyst.

Metal-Free Twofold Electrochemical C-H Amination of Activated Arenes: Application to Medicinally Relevant Precursor Synthesis.

The efficient production of many medicinally or synthetically important starting materials suffers from wasteful or toxic precursors for the synthesis. In particular, the aromatic non-protected primary amine function represents a versatile synthetic precursor, but its synthesis typically requires toxic oxidizing agents and transition metal catalysts. The twofold electrochemical amination of activated benzene derivatives via Zincke intermediates provides an alternative sustainable strategy for the formation of new C-N bonds of high synthetic value. As a proof of concept, we use our approach to generate a benzoxazinone scaffold that gained attention as a starting structure against castrate-resistant prostate cancer. Further improvement of the structure led to significantly increased cancer cell line toxicity. Thus, exploiting environmentally benign electrooxidation, we present a new versatile and powerful method based on direct C-H activation that is applicable for example the production of medicinally relevant compounds.

Identification of therapeutic peptide scaffold from tritrpticin family for urinary tract infections using in silico techniques.

Antimicrobial peptides (AMPs) like tritrpticins, exhibit non-specific membrane lysis of gram-negative bacteria and can replace antibiotics, combating multi-drug resistance observed in UTI patients. Tritrpticins designated - NT, T1, T2, T3, T5, T7 and T8, were computationally investigated by interaction with Escherichia coli membrane model, mammalian cell toxicity and structural stability to identify a potential drug scaffold for UTI. Initially T3 was eliminated due to low interaction with Escherichia coli membrane model, based on its computed solvation energy. Further, negative support vector machine (SVM) scores revealed non-toxicity of T1, T2, T5, T7 and T8. Finally, at 310 K and varying pH 4.5-9.0, T5 exhibited highest structural stability based on its highest consistency of hydrogen bonds (H-bonds), root mean square deviation (RMSD) and secondary structure profiles along with its lowest conformational free energy. Overall, T5 could be considered a promising peptide drug scaffold to combat UTI.ABBREVIATIONSAMPantimicrobial peptidePBEQPoisson Boltzmann equationH-bondshydrogen bondsMICminimum inhibitory concentrationLD50lethal dose, 50%RMSDroot mean square deviationSVMsupport vector machineUTIurinary tract infectionCommunicated by Ramaswamy H. Sarma.

Hydrogen bonds in anoplin peptides aid in identification of a structurally stable therapeutic drug scaffold.

Multi-drug resistance is a major issue faced by the global pharmaceutical industry. Short antimicrobial peptides such as anoplins can be used to replace antibiotics, thus mitigating this issue. Antimicrobial activity, non-toxicity, and structural stability are essential features of a therapeutic drug. Antimicrobial activity and toxicity to human erythrocytes have been previously reported for anoplin and anoplin R5K T8W. This study attempts to identify a therapeutic peptide drug scaffold between these peptides by examining their structural stability, mainly based on the hydrogen bonds (H-bond) found in their structures. The static structure of anoplin R5K T8W displayed lower H-bond distances than anoplin, thereby exhibiting enhanced structural stability. Dynamic stability studies revealed that conformers of anoplin R5K T8W exhibited lower hydrogen bond distances (HBDs), higher H-bond occupancies, and higher radial distribution function (RDF) of H-bonds in comparison with conformers of anoplin. Furthermore, conformers of anoplin R5K T8W generated using 50-ns molecular dynamics simulation displayed lower conformational free energy than anoplin, thus establishing its higher structural stability. Overall, anoplin R5K T8W can be claimed as a promising scaffold that may be used for therapeutic purposes. In conclusion, H-bonds play a major role in structural stability and may aid in identification of a therapeutic peptide scaffold. Graphical abstract.

Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold.

Oral activity has been described for cyclotide-containing traditional medicines, and demonstrated for reengineered cyclotides bearing grafted therapeutic epitopes, highlighting their potential for translation to the clinic. Here we report preclinical pharmacokinetic parameters for the prototypic cyclotide kalata B1 (kB1) and two orally active grafted analogues, ckb-KAL and ckb-KIN, to provide the first in vivo dose-exposure metrics for cyclotides. Native and grafted kB1 molecules exhibited multiple compartment kinetics and measurable but limited oral bioavailability of similar magnitude to several orally administered peptide drugs in the clinic. Cyclotides are mostly associated with the central compartment, and display small (0.07-0.13 L kg-1 for kB1 and ckb-KIN) to moderate (1 L kg-1 for ckb-KAL) steady state volumes of distribution. This study provides new data essential to the evaluation of cyclotides as therapeutics, validating them as a viable drug design scaffold with tunable pharmacokinetic properties.