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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
Other nitroheterocycles investigated for their antichagasic activity include indazole-based derivatives. A series of 3-alkoxy-1-alkyl-5-nitro-1H-indazoles were evaluated against the CL-Brener clone of T. cruzi epimastigotes, affording moderately active derivatives (51) (Figure 12) (Rodríguez et al. 2009a, b). Closely related analogs in 5-nitroindazolin-3-one series showed interesting sub-micromolar activity for the compound (52) (Vega et al. 2012, Fonseca-Berzal et al. 2016a). Varying the 1-alkyl chain led to a marked improvement in the anti-Trypanosoma cruzi activity, which became as potent as the reference drug benznidazole (9). SAR analysis suggests that electron-donating groups at position 1 of the indazolinone ring are associated with improved antichagasic activity. Compound (53), although only moderately active on the epimastigote form, was very efficacious against amastigotes from CL-Brener as well as Tulahuen and Y strains of T. cruzi (IC50 = 0.22, 0.81 and 0.60 μM, respectively), and showed low cytotoxicity against fibroblasts and cardiac cells (Fonseca-Berzal et al. 2016b). The SAR analysis suggests that electron-donating groups at position 1 of the indazolinone ring are associated with improved antichagasic activity. When the water-soluble amino group was introduced (54), there was a great improvement of the activity on the epimastigote form of the parasite and the activity on the amastigote form was also very potent (IC = 0.25 μM). In addition, (54) was active against other T. cruzi strains without cytotoxicity on fibroblastic or cardiac cells (Aran et al. 2018). Structure of compounds (51–53) is shown in Figure 12. Structures and in vitro activities of 5-nitroindazole derivatives against epimastigote T. cruzi.
Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways
Published in Neurological Research, 2022
Hossein Ghorbanzadeh, Parastoo Mohebkhodaei, Mehran Nematizadeh, Nastaran Rahimi, Mahsa Rafeiean, Mehdi Ghasemi, Ahmad R. Dehpour
Modafinil, 7-nitroindazole (7-NI; a selective nNOS inhibitor), citalopram (a selective serotonin reuptake inhibitor; SSRI), aminoguanidine (a selective inducible NOS inhibitor), and L-NG-nitroarginine methyl ester (L-NAME; a nonspecific NOS inhibitor) were purchased from Sigma-Aldrich (Germany). Xylazine and ketamine were purchased from Alfasanco (Woerden, Holland) and dimethylsulfoxide (DMSO), Tween 80, and formalin solution were bought from Merck Company (UK). Modafinil suspension was made using tween 80 1%. 7-NI was dissolved in DMSO 10%. Other chemicals were dissolved in saline. All drugs were prepared freshly before the experiments and injected intraperitoneally (i.p.) in a volume of 10 ml/kg. Mouse-specific enzyme-linked immunosorbent assay (ELISA) kits for measuring IL-6 and TNF- α were bought from DuoSet (R&D systems, United States). Nitric Oxide assay kit was bought from ZellBio GmbH (Germany).
Exposure to Static and Extremely-Low Frequency Electromagnetic Fields and Cellular Free Radicals
Published in Electromagnetic Biology and Medicine, 2019
This is a review of the research on the effects on cellular free radicals after exposure to static- and extremely-low frequency (ELF, 0–300 Hz) non-ionizing electromagnetic field (EMF). In 1997, we first reported that melatonin, a potent antioxidant, and the spin-trap compound N-tert-butyl-alpha-phenylnitrone (that neutralizes free radicals) blocked a 60-Hz magnetic field-induced DNA strand break in cells of the rat brain (Lai and Singh 1997a, 1997b). Further experiment (Lai and Singh 2004) demonstrated similar inhibitory effects of Trolox (a vitamin E-analog anti-oxidant) and 7-nitroindazole (a nitric oxide synthase inhibitor). In addition, the effect could also be blocked by the iron chelator deferiprone suggesting the involvement of the iron-catalyzed Fenton Reaction that produces the potent cytotoxic hydroxyl free radical. These data indicated that the ELF magnetic field affected free radicals in cells leading to cellular molecular damages. There are now more than 200 papers published showing that static and ELF-EMF affect cellular free radical processes. A list of the papers is in the “supplementary material” included in the on-line version of this paper. There are rather strong indications that exposure to static- and ELF-EMF affects oxidative status in cells and animals. Many of the cellular oxidative and anti-oxidative components have been shown to be affected by the fields.
Lamotrigine as a mood stabilizer: insights from the pre-clinical evidence
Published in Expert Opinion on Drug Discovery, 2019
Aline Silva de Miranda, Amanda Silva de Miranda, Antônio Lúcio Teixeira
Nitric oxide (NO) synthesis from its precursor L-arginine by nitric oxide synthase (NOS) is dependent on the activation of NMDA receptors [90,91]. Therefore, it is reasonable to hypothesize that antidepressant properties of LTG might also be mediated by NO-dependent mechanisms. Antidepressant-like effects of NOS inhibitors have been demonstrated in previous studies [92–94]. Sub-effective dose of L-arginine (750 mg/kg, i.p., a substrate for NOS) injected in mice 30 min before the effective dose of LTG (10 mg/kg, i.p.) reversed its antidepressant-like effect in the FST. When sub-effective dose of LTG (5 mg/kg, i.p.) was co-administered with sub-effective doses of L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p., a non-specific NOS inhibitor) or 7-nitroindazole (7-NI, 30 mg/kg, a neuronal NOS inhibitor), there was decrease in the immobility time in the FST. Taken together, these findings support a role for NO in LTG-associated antidepressant actions [86].