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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Nilutamide is eliminated exclusively by metabolism, the main pathway involving initial reduction of the aromatic nitro group. Hydrolysis of one of the carbonyl functions of the imidazolinedione ring has also been shown to occur, but to a much lesser extent than cleavage of the equivalent amide bond in hydroxuflutamide. This contributes to the longer half-life of nilutamide in humans of approximately two days. The nitro anion-free radical formed during reduction of the nitro group is thought to be related to the hepatotoxicity observed in humans, especially at high dose levels.
The Renewal of Interest in Nitroaromatic Drugs
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Nicolas Primas, Caroline Ducros, Patrice Vanelle, Pierre Verhaeghe
Anti-infective nitroheterocycles act as prodrugs requiring the bioactivation of their nitro group before presenting antibacterial or antiparasitic properties (Blumer et al. 1980). While this nitro group is mandatory to the activity of this family of molecules, diverse substituents on the other positions of the heterocyclic ring may allow the modulation of their spectrum of activity and physicochemical parameters (Goldman 1982). The recognized mechanism of action for 5-nitroimidazoles first involves their penetration into the target cell by passive diffusion, followed by the reduction of the nitro group into Reactive oxygen species (ROS), including radical species (Race et al. 2005). Finally, the reaction of these reactive metabolites with cellular components such as DNA or proteins forms covalent adducts leading to the death of the infective agent (Azam et al. 2015). The reduction of nitroimidazole drugs by microorganisms is governed both by the reduction potential of the molecule and the number of electrons involved in the reduction (Edwards 1993, Spain 1995). In kinetoplastids, the enzymes catalyzing this type of reaction are called nitroreductases (NTR) (Fairlamb and Patterson 2018).
Barbiturates And Minor Tranquilizers
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
As discussed in the preceding section, a modification of parent structure with different sub-stitutents on the 1, 3, 5, and 7 position results in the formation of a variety of compounds with quantitative differences in pharmacologic activity.34,49,50,61,62,67 If the hydrogen at the number 1 position of the “B” ring is replaced with an electron-withdrawing group (Table 3) such as a chloro, bromo, fluoro, cyano, nitro, or a trifluoro-methyl group, the potency of the parent molecule is increased. A nitro group has stronger electron-withdrawing properties than a chloro group, and a molecule bearing the former substituent is more potent than the chloro derivative. The electron-releasing groups, like methyl and dimethylamino, tend to decrease the effectiveness of the molecule, whereas a mercapto group increases the potency.62 In addition, a saturation of the 4 to 5 double bond of the “B” ring by catalytic hydrogenation reduces the effectiveness of the compound when compared to compounds bearing the unsaturated double bond, regardless whether the derivative possesses an electron-withdrawing or releasing substituent.62
A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Wenjing Liu, Min He, Yongjun Li, Zhiyun Peng, Guangcheng Wang
The nitro group is a unique functional group. Its strong electron attraction ability produces local or local electron defects in the molecule, which enables the part with a strong electrophilic ability to bind closely to amino acids, proteins, and enzymes. The introduction of the nitro group enables compounds to have a variety of chemical and biological effects. For example, Zhang and co-workers obtained a series of compounds 69 (Figure 45) by introducing o-nitroaromatic rings into chalcone and evaluated for their biological activities as anti-tubulin agents136. All of them showed significant activities against tubulin polymerisation and the growth of MCF-7 and A549 cell lines. Thereinto, compound 69a had the strongest inhibitory activity against MCF-7 and A549 cells (IC50 = 0.03 and 0.95 µg/mL) and was the best compound in the anti-tubulin polymerisation assay with IC50 of 1.42 µg/mL. SAR analysis indicated that the antiproliferative activity of the electron substituents introduced into the A ring was stronger than that of the electron-withdrawing substituents, and the potency order was CH3 > OCH3. However, compounds of salicylaldehyde have two halogen atoms at position-3 and position-5, their anticancer activity was lower than that of introducing only one halogen atom at position-5. In the molecular docking study, one hydrogen bond and one π-cation of 69a could interact with the colchicine binding site protein residues, which might play a key role in its anti-tubulin polymerisation and anti-proliferative activities.
Identification of structural fingerprints for in vivo toxicity by using Monte Carlo based QSTR modeling of nitroaromatics
Published in Toxicology Mechanisms and Methods, 2020
Dipayan Mondal, Kalyan Ghosh, Anurag T. K. Baidya, Anindita Mondal Gantait, Shovanlal Gayen
In the nitroaromatics, oxygen atoms bonded with nitrogen atom are more electronegative than nitrogen. This results in polarization of the oxygen–nitrogen bond and thus, nitro groups possess more electronegative character. As a result, nitro groups are themselves reduced by taking part in oxidation reactions and produce the biologically inert polymeric compounds, e.g. azo, azoxy compounds (Kulkarni and Chaudhari 2007). In our body, the normal functions of some proteins and DNA are blocked by the nitroaromatic compounds as these compounds can combine with the nucleophilic sites (examples –OH, −SH, and NH2 groups) through nucleophilic aromatic substitution (Katritzky et al. 2003). They can also form a complex with electron-donating heterocycles in biomolecules and may alter their normal function. In oxidative phosphorylation, they may also act as an uncoupling agent and may lead to a complex mechanism of toxicity (Donlon et al. 1995).
Cheminformatics and virtual screening studies of COMT inhibitors as potential Parkinson’s disease therapeutics
Published in Expert Opinion on Drug Discovery, 2020
Kalliopi Moschovou, Georgia Melagraki, Thomas Mavromoustakos, Lefteris C. Zacharia, Antreas Afantitis
In silico tools could play a significant role in supporting the effort of identifying novel COMT inhibitors or improving the properties of existing inhibitors. As evidenced from the literature, a substantial amount of work has been done on COMT inhibitors which has increased the knowledge on the efficacy and suitability of various types of inhibitors as potential therapeutics, and the specific functional groups of a molecule that are likely to affect efficacy and toxicity. The issue of increasing half-life has been addressed by many experimental attempts, while there is room for improvement. However, more efforts are needed to minimize the side effects. Interestingly the bisubstrate inhibitors seem to alleviate toxicities if the nitro group is removed which is necessarily present in all three nitrocatechol inhibitors currently in the market. This by itself provides the framework for future research. With the knowledge gained from the in vitro and in vivo behavior of different inhibitors, and the modifications afforded and tested in silico by chemoinformaticians are challenged to integrate this knowledge to design novel inhibitors that are substantially better tolerated. Given that computer-aided drug design seems to be at its peak performance, this provides a unique opportunity for realization of the drug optimization, without of course minimizing the challenges that reflect the in silico to in vivo translation.