The Renewal of Interest in Nitroaromatic Drugs
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
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
S.J. Mulé, Henry Brill in 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
Nitric Oxide as a Mediator of Intestinal Mucosal Function
T. S. Gaginella in Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Chemiluminescence techniques can detect NO directly in the gaseous phase.11Extracting NO from a biological solution before it is oxidized is fraught with problems. Nitrite, nitrate, and other bound/oxidized forms of oxidized NO can be converted back to gaseous NO in purge chambers (e.g., boiling, vanadium chloride acidified to pH 1.0). The NO formed in this reduction process is then directed to the NO detector in a nitrogen or helium carrier. A problem lies in the efficiency by which this process releases NO from binding sites. For example, NO is formed from the reduction of the nitro group on the NOS inhibitor NG-nitro-l-arGinine (l-NNA) or its methyl ester. Thus, this method may Give a false positive reading when animals/solutions have been treated with l-NNA or NG-monomethyl L-arGinine (l-NMMA). It will also release NO bound to thiol Groups in albumin; thus plasma readings are hiGher than those from serum. However, the chemiluminescent approach is equally sensitive and requires small sample sizes, as low as 50 μl.
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.
Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Yao Chen, Jie Zhu, Jun Mo, Hongyu Yang, Xueyang Jiang, Hongzhi Lin, Kai Gu, Yuqiong Pei, Liang Wu, Renxiang Tan, Jing Hou, Jingyi Chen, Yang Lv, Yaoyao Bian, Haopeng Sun
Next, we examined the optimal substituents on cinnamic acid moiety. Methyl substitution at meta- or ortho- position of cinnamic acid (14 and 15, respectively) led to the reduced activities compared to compound 12, but the para-substituted compound 16 showed comparable activity to 12. We further examined the inductive effects of the substituents on the ChEs inhibitory activity. The nitro group was introduced to act as an electron-withdrawing group. Data showed that the nitro group could remarkably improve the activity of the compounds. The para-substituted 19 was the most potent compound (AChE IC50 = 2.7 ± 0.4 nM, BuChE IC50 = 6.5 ± 0.6 nM). When the nitro group was replaced by -CF3, compounds were less potent than 12, except for the para-substituted compound 23. Interestingly, the effects of methyl, nitro and -CF3 substitution on ChEs activity showed a consistent manner: for AChE, the activity was para- > meta- > ortho-, while it showed an opposite manner on BuChE. The results indicated that the para-position was optimal for the design of potent AChE inhibitor.
Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jing-Wei Liang, Ming-Yang Wang, Shan Wang, Shi-Long Li, Wan-Qiu Li, Fan-Hao Meng
The proliferation experiment of Compound 1 and Compound 3 against HCT116 and A549 was also carried out. Compound 1 showed preferable inhibitory activity against both HCT116 and A549, especially against HCT116 with IC50 value of 7.2 ± 1.4, which was equivalent to the positive drug Milciclib, while Compound 3 only showed inhibitory activity against HCT116. Besides, the inhibitory activity was not as good as that of Compound 1 (Table 7). Comparing the structural characteristics of the two compounds, it was found that Compound 3 contained a nitro group. The group possessed strong polarity, its introduction made it difficult for small molecules to penetrate the cell membrane. This might be the reason that two compounds with similar inhibitory activity at the protein level differ greatly at the cell level.
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