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Antiviral Agents and Rational Drug Design
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The importance of the dimer nature of the protease enzyme is evident in these mechanisms, as the two equivalent aspartate residues, Asp-25 and Asp-25’ work cooperatively to catalyse the hydrolysis of the amide bond of the isostere shown explicitly here without convolution from drawing the rest of the substrate structure. This is an acid-base mechanism, using water as a nucleophile, which is activated by the Asp-25’ residue. The TS intermediate (2) is an unstable structure, so the challenge for medicinal chemists was to incorporate this tetrahedral TS isostere into a molecular scaffold to produce a stable compound that would perform as an effective drug.
Radiochemistry for Preclinical Imaging Studies
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Fluorine is an isostere for the hydroxy group. The replacement of aromatic hydrogen with fluorine renders the molecule more lipophilic, whereas the addition of fluorine to aliphatic moieties increases the polar character of the molecule (Purser et al. 2008). Fluorine-18 can be conjugated to molecules of interest in many ways. As mentioned earlier, the cyclotron provides fluorine-18 either as [18F]F2 gas or as [18F]F− ion. The former has the drawback of being carrier-added, that is, the reaction product will be diluted with nonradioactive fluorine-19. In addition, [18F]F2 gas will be very reactive and thus show only little substrate selectivity. On the other hand, [18F]F− shows only poor reactivity as a nucleophile and will have to be activated. The high reactivity of [18F]F2 is usually reduced by producing a hypofluorite intermediate through reaction with acetic acid (Figure 16.13).
Phosphonic Acids And Phosphonates As Antimetabolites
Published in Richard L. Hilderbrand, The Role of Phosphonates in Living Systems, 2018
The implication of an isosteric relationship between a natural phosphate and a phosphonic acid wherein a methylene group is present in place of the normal esteratic oxygen requires close consideration. In the strictest sense, the term “isosteric” refers to compounds of identical size and shape. However, crystallographic data13,17 for simple related phosphate esters and phosphonic acids indicate there to be nontrivial differences in the following comparisons: C–O–P and C–C–P bond angles; O–P–O and C–P–O bond angles; C–O and C–C bond distances; and O–P and C–P bond distances. In spite of these nontrivial differences it is found that there is only very minor variation in distances between phosphoryl or phosphonyl oxygen and distant functional groups for corresponding conformations. This is simply a fortuitous consequence of effects being in opposite directions.
Identification of sulphonamide-tethered N-((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mai H. ElNaggar, Abdullah A. Elgazar, Ghada Gamal, Shimaa M. Hamed, Zainab M. Elsayed, Mohamed K. El-Ashrey, Amira Abood, Mahmoud A. El Hassab, Ahmed M. Soliman, Ramadan A. El-Domany, Farid A. Badria, Claudiu T. Supuran, Wagdy M. Eldehna
The data listed in Table 1 disclosed that the examined 3CL-Pro was inhibited by the herein described triazolo isatins in a variable degree. The target sulphonamide-tethered triazolo isatins 6a-d effectively inhibited 3CL-Pro with IC50 values spanning from 0.249 to 1.054 μM. Compounds 6a-c showed the ability to exert sub-micromolar inhibition; IC50 equal 0.562 ± 0.005, 0.249 ± 0.006 and 0.939 ± 0.007 μM, respectively, whereas compound 6d displayed low-micromolar inhibitory activity (IC50 = 1.054 ± 0.053 μM). Incorporation of unsubstituted isatin motif resulted in compound 6a with good inhibitory activity (IC50 = 0.562 μM). Fluorine is exploited as an isostere for the hydrogen atom since its similar to hydrogen in terms of size and electronic characteristics. Triazole derivative 6b bearing fluorine substituent at the isatin C-5 showed an increase in the 3CL-Pro inhibitory activity suggesting that the C-5 substitution is tolerated and also highlighting that the halogens incorporation may be advantageous. Moreover, grafting methoxy or trifluoromethoxy group led to compounds 6c and 6d with about 2-fold decreased activity (IC50 = 0.939, and 1.054 μM, respectively) than their unsubstituted counterpart 6a.
Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development
Published in Drug Metabolism Reviews, 2022
Siva Nageswara Rao Gajula, Tanaaz Navin Nathani, Rashmi Madhukar Patil, Sasikala Talari, Rajesh Sonti
Metabolic stability data is essential for evaluating and optimizing the human therapeutic dose. Improved metabolic stability of the drug enhances its plasma half-life and reduces dosing frequency (Gajula et al. 2021). The knowledge of liable sites for metabolism aids in deciding structural changes to impart metabolic stability to the drug molecules. The specific structural features of drug molecules can be attributed to their susceptibility toward AO mediated metabolism. For instance, drugs with at least one aromatic nitrogen-containing heterocycle with an unsubstituted aromatic carbon atom adjacent to the nitrogen atom are potential substrates for AO (Pryde et al. 2010). The polarity of the drug can be increased by incorporating isosteric functional groups at the metabolic site, thereby reducing the AO mediated metabolism (Gajula et al. 2021). Medicinal chemists are attempting to reduce lipophilicity by introducing polar nitrogen-based heterocyclic rings. These heterocyclic rings are essential for binding kinase inhibitors to the ATP binding ‘hinge’ region of the kinase domain. However, this strategy in synthesizing kinase inhibitors alleviates P450 metabolism but increases the AO metabolism (Pryde et al. 2010). Furthermore, blocking or modification of metabolically liable groups enhances metabolic stability. For AO substrates, several strategies available to reduce AO susceptibility are direct blocking of the oxidation site, replacing the affected carbon with a heteroatom, removing nitrogen, and saturation of aromatic and unsaturated azaheterocycles (Manevski et al. 2019).
Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
The origins of bioisosterism can be traced back to observations from Langmuir in 1919 noting that the physical properties of certain chemically different substances – for example CO and nitrogen – are very similar [59]. This apparent similarity was attributed to the fact that both CO and nitrogen have 14 orbital electrons, and thus with the same number of atoms the octet theory of valence indicates that these electrons may arrange themselves in the same manner. The concept of isosterism was thus defined as follows: ‘Comolecules are thus isosteric if they contain the same number and arrangement of electrons. The comolecules of isosteres must, therefore, contain the same number of atoms. The essential differences between isosteres are confined to the charges on the nuclei of the constituent atoms.’ In the initial report, Langmuir cited 21 kinds of isosteres and it is important to note that whereas isosterism does not necessarily imply that structures have the same total electric charge (isoelectronic), derivatives that do (cf. CO and N2) show the closest match in properties. Within the original study, Langmuir also predicted analogies between ketene and diazomethane (each with 22 orbital electrons) that were only experimentally observed later.