China
Africa
Explore chapters and articles related to this topic
Central Nervous System Effects of Essential Oil Compounds
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Elaine Elisabetsky, Domingos S. Nunes
A couple of compounds that also wait for comparative structure-activity-mechanism of action studies is formed by linalool 9 (C10, monoterpene) and nerolidol 10 (C15, sesquiterpene). These are tertiary alcohols with α,β-unsaturation to the carbon that bears the hydroxyl group. The extremities of the open chains of these two alcohols are identical: a tertiary hydroxyl on one side and an isoprenic C5 unity on the other. Both present an asymmetric center in the tertiary carbon and may be present in EOs with only one optic isomer (R or S) or as a mixture of the two. Another factor to consider is that nerolidol 10 has cis-trans isomerism in the double bond C6–C7, which increases the number of possible isomers and conformers.
Oxyfunctionalization of Pharmaceuticals by Fungal Peroxygenases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Jan Kiebist, Martin Hofrichter, Ralf Zuhse, Katrin Scheibner
Ibuprofen (12) is a non-steroidal anti-inflammatory drug (NSAID) commonly prescribed for its anti-inflammatory, analgesic, and antipyretic properties. Following oral administration of 12, 60% of the dose was recovered in urine samples as 2-hydroxyibuprofen (13), 3-carboxyibuprofen and their conjugates, suggesting that mainly human P450 CYP2C9 is involved in its metabolization (Hamman et al., 1997). When using UPOs (MroUPO, CglUPO, AaeUPO), the isobutyl side chain of 12 was hydroxylated at the tertiary carbon as well to form the human main metabolite 13 (by 82%, 80% and 48%, respectively) (Kiebist, 2018). In the latter case, additionally, the benzylic oxidation products, 1-hydroxyibuprofen (14) and 1-ketoibuprofen (15), were detected (Fig. 18.9), which both are also known as human metabolites (Holmes et al., 2007). UPO-catalyzed oxidation of ibuprofen by [a] AaeUPO, [b] MroUPO and [c] CglUPO.
Organotin Chemistry
Published in Nate F. Cardarelli, Tin as a Vital Nutrient:, 2019
In the third category are compounds in which a tertiary carbon atom is replaced by one of silicon, a C−O−C linkage is substituted by its Si−O−C analog, or an R3CH is replaced by an R3SiH group. The last named are hydrolytically unstable and are utilized in pro-drugs. However, −Si(CH3)2− linkages can also be used to replace −CH2− groups and alter steric effects.
Validation of the OptiSafe™ eye irritation test
Published in Cutaneous and Ocular Toxicology, 2020
Neepa Choksi, Stewart Lebrun, Minh Nguyen, Amber Daniel, George DeGeorge, Jamin Willoughby, Adrienne Layton, Donnie Lowther, Jill Merrill, Joanna Matheson, João Barroso, Krystle Yozzo, Warren Casey, David Allen
To investigate commonalities among false positive and false negative chemicals, structural features were identified and evaluated. The Organic Functional Group profiler in the OECD Toolbox (v 4.1), a quantitative structure–activity relationship program, was used to identify structural fragments in the tested chemicals19 (Supplemental Tables). It is noted that a single chemical may be assigned to more than one structural feature group. Isopropyl was the only structural feature group with a 100% (2/2) EPA false positive rate based on more than one chemical (Supplemental Tables). Other structural feature groups having EPA false positive rates of at least 50% and at least two chemicals in the chemical class included aldehyde (1/2), alkane branched with a tertiary carbon (1/2), alkene (1/2), allyl (1/2), aryl (2/4), dihydroxyl derivatives (1/2), thiol (1/2), carboxylic acid ester (2/3), and ether (3/4). A similar pattern was observed for the GHS false positives (Supplemental Tables).
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
One of the major challenges for the direct reaction of C–H bonds is site-selectivity, as most organic compounds possess many similar C–H bonds. Most procedures rely on substrate control where one particular C–H bond is more reactive than the others. However, a more general method would be to use catalyst control to afford selectivity akin to how nature uses enzymes to selectively functionalize certain C–H bonds. The Davies group has recently developed methods for the site-selective and stereoselective functionalization of unactivated C–H bonds [48,49]. In 2017 they disclosed a rhodium-carbene-induced C–H insertion at the most accessible tertiary C–H bond (Figure 4(e)) [49]. It is demonstrated that site-selectivity is catalyst dependent and judicious choice of catalyst, in this case Rh2(S-TCPTAD)4, affords C–H functionalization of cholesteryl pelargonate at the most accessible tertiary carbon as a single diastereomer in the presence of many C–H bonds.
Recent advances in mycobacterial membrane protein large 3 inhibitor drug design for mycobacterial infections
Published in Expert Opinion on Drug Discovery, 2023
E. Jeffrey North, Chris P. Schwartz, Helen I. Zgurskaya, Mary Jackson
Urea-based inhibitors have been evaluated after lead urea AU1235 [Table 3] was first identified as an MmpL3 inhibitor [21,57,58]. The urea scaffolds have two bulky hydrophobic groups on the two nitrogen atoms of the urea core. On each side of the urea core, AU1235 has a 2-adamantyl group and a 2,3,4-trifluorophenyl group. The nitrogen atoms are in the center of the compound similar to the other cores (SQ109, indole-2-carboxamides, acetamides). One interesting thing about the adamantyl group is that it only has two different types of carbons (secondary and tertiary). The nitrogen is attached to the secondary carbon of the adamantyl group in AU1235, but analogues have been synthesized that have the urea attached to the tertiary carbon instead and have only been slightly effective [58]. Analogues with different substituents on both sides have varied effects on the MICs [58]. Substitutions include other bicyclic and cyclic alkyl groups instead of the adamantyl group and various aromatic and heteroaromatic groups. From examples shown in Table 3, there are a few things that seem to be important. First, the adamantyl group attached to the secondary carbon (22, AU1235) rather than the tertiary carbon (23) elicits more potent MIC values. Second, if the adamantyl group is replaced with a different alkyl group, it appears as though it should be a large bulky cycloaliphatic group (25, 26, 28 – 30). Symmetric cycloaliphatic groups seem to boost potency as well. Third, aromatic substitutions lead to a relatively flat SAR. Meta- and para-substitutions of various electrostatic and steric functional groups were tolerated (25, 26). Only ortho-substitutions, other than H or F, were detrimental to antimicrobial action (27). Five-membered ring heteroaromatics were excellent bioisosteres for the phenyl ring which resulted in good antitubercular activity and improved aqueous solubility (28 – 30) [58]. Pyridine (31), pyrimidine, and triazine were detrimental to activity. Poor aqueous solubility is the major physicochemical property likely limiting this series translational development. To date, no in vivo PK or efficacy studies have been reported for urea-based MmpL3 inhibitors.