Other Experimental Antiepileptic Drugs
Stanley R. Resor, Henn Kutt in The Medical Treatment of Epilepsy, 2020
The anticonvulsant activity of benzyhydryl piperazines has been known for over 20 years (1). One of the original compounds, ropizine, was extensively studied for several years before its development was abandoned because of toxic trace impurities derived in its synthesis. Desmedt and coworkers (2) subsequently described the anticonvulsant activity of flunarizine (FNR) (molecular weight 477.42) and cinnarizine in mice and rats. (See structures for ropizine, flunarizine, and cinnarizine on p. 662.) These compounds have similar activity in preventing seizure spread with little or no effect on raising seizure threshold. The ED50 for abolishing electrically induced hindlimb tonic extension in rats was 2.3 mg/kg for ropizine (3,4) and 6.0 mg/kg for FNA and 19 mg/kg for cinnarizine (2). FNR and cinnarizine also prevent the hindlimb tonic extension produced by intravenous administration of pentylenetetrazol (80 mg/kg) in rats. There is little or no effect of any of these drugs on clonic seizures produced by the chemical convulsants. The anticonvulsant profile of this class of compounds is similar to that seen with phenytoin (PHT) and carbamazepine (CBZ).
Licit and illicit drugs
Jason Payne-James, Richard Jones in Simpson's Forensic Medicine, 2019
Many of these newly abused drugs belong to the chemical class known as piperazines, derived from piperazine and benzyl chloride. Piperazines were originally used as worming agents in humans and in veterinary medicine, particularly in the treatment of round worms (especially Ascaris); they paralyse the worms so they are flushed out by peristalsis. However, the medicinal use of piperazines is banned in many countries. Ironically, more than half of the cocaine sold in the USA is contaminated with levamisole, a piperazine anti-helminthic drug, which was initially withdrawn from the US market because it is known to induce bone marrow suppression. Several piperazines derivatives are now in circulation.
NPS in Emergency Rooms
Ornella Corazza, Andres Roman-Urrestarazu in Handbook of Novel Psychoactive Substances, 2018
A complete set of exams is mandatory to evaluate and treat possible complications of psychoactive abuse, such as rhabdomiolisis in piperazines abuse or renal and urinary toxicity due to exposure to dissociative substances. More detailed laboratory tests, like hormonal profile, can be useful too, since some studies have shown higher values of cortisol, oxytocin, and prolactin in MDMA and DMT users (Parrott et al., 2014; Mas et al., 1999; Santos & Strassman, 2011), but most of these findings are anecdotal and their diagnostic or clinical value is limited at the moment, especially in an ER setting.
Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xiao-Yi Shi, Huang Jiao, Jia-Kai Zhang, Xin-Yi Tian, Dan-Feng Guo, Jie Gao, Mei-Qi Jia, Jian Song, Sai-Yang Zhang, Xiang-Jing Fu, Hong-Wei Tang
We further explored the effects of replacement of aryl piperazine groups with alkyl piperazines, carbonyl piperazines, morpholine, or thiomorpholine on the antiproliferative activities. As shown in Table 2, the target compounds 16l–16s exhibited reduced antiproliferative activities with IC50 values ranging from 0.88 to 6.69 μM than that of compounds 16a–16k. Among them, compound 16l bearing the 1-methylpiperazine group exhibited the most potent inhibitory activities with IC50 values of 1.21 (for MGC-803), 0.88 (for HCT-116), and 1.58 μM (for SMMC-7721). Comparing the antiproliferative activities of compounds 16l–16s, it was obvious to figure out that the compounds 16l–16o bearing the alkyl piperazines were more effective in inhibiting the proliferation of cancer cells than that of compounds 16p–16s bearing the carbonyl piperazines (compounds 16p–16q), morpholine (compound 16r), or thiomorpholine (compound 16s). In addition, the extension of alkyl chains (compounds 16l–16o) reduced inhibitory activities.
The piperazine scaffold for novel drug discovery efforts: the evidence to date
Published in Expert Opinion on Drug Discovery, 2022
Maria Novella Romanelli, Dina Manetti, Laura Braconi, Silvia Dei, Alessio Gabellini, Elisabetta Teodori
The widespread insertion of a piperazine moiety into drugs is due to its physicochemical properties. Piperazine 20 (Table 2) contains two basic nitrogen atoms; however, at physiological pH (7.4), only one is protonated (pKa values 9.75 and 5.36) [18]). The basicity of substituted piperazines varies according to the position and nature of the substituent. In fact, 20 becomes less basic after alkylation of one carbon atom (20a) and of one (20b, 20c) or of both nitrogen atoms (20d) [19]. The insertion of acyl (20e-h) or sulfonyl (20i) substituents, or of aromatic rings (20 j-l), is also detrimental [20–22]: the pKa variation depends on the kind of aryl group and the substituent on the aromatic ring [20,21]. The reduction of basicity after alkylation of one of the N atoms was verified also in other situations [20,22]. For instance, we can compare the pKa of 20f and 20h or 20j and 20k. The basicity obviously affects the degree of ionization of the molecule, its lipophilicity and solubility, and its ability to establish H-bonds as donor or acceptor, in other words, its drug-like properties.
A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zhe Zhang, Zhao-Sheng Zhang, Xiao Wang, Gao-Lei Xi, Zhen Jin, You-Zhi Tang
First of all, we borrowed from the previous work experience of the laboratory18–20,22 and introduced methylpiperazine and phenylpiperazine in the C-14 side chain. In order to explore SAR, different electron withdrawing groups (chlorine, fluorine, nitro and hydroxy) and donating groups (methyl and methoxy) were introduced on the benzene ring of compound 49. Most of the derivatives of compound 49 reserved moderate to strong antibacterial activities, with compounds 50, 56, 62 and 64 displaying potent antibacterial activity against MRSA. The substituted piperazine derivatives 50–52, 62–64 bearing optimum substituents, including methyl and nitro groups, exhibited relatively high inhibitory activities against all the tested strains. Among them, compound 64 which bearing 4-nitrophenyl piperazine group on the C-14 glycolic acid side chain possessed the highest antibacterial activities against MRSA (MIC = 0.5 µg/mL) in this series, being comparable to tiamulin. This may be explained by the strong electron-withdrawing ability of the nitro group, which can generate local electron-deficient sites in the molecule and interact with proteins and amino acids present in the living system27. However, other kinds of substituents or other substituent sites may weaken these effects.
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