European Journal of Medicinal Chemistry最新文献

{"title":"Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines","authors":"David D. N'Da ,&nbsp;Janine Aucamp ,&nbsp;Helena D. Janse van Rensburg ,&nbsp;Keisuke Suganuma","doi":"10.1016/j.ejmech.2024.116979","DOIUrl":"10.1016/j.ejmech.2024.116979","url":null,"abstract":"<div><div>Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (S_N), hydrazination and Schiff base condensation reactions, and was evaluated against various <em>Leishmania</em> and <em>Trypanosoma</em> species and strains. Several promising hits portraying leishmanicidal and trypanocidal with <em>in vitro</em> submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine <strong>11</strong> (<em>Tc</em> IC₅₀: 0.08 ± 0.03 μM) and nitrothienylazine <strong>13</strong> (<em>Tc</em> IC₅₀: 0.09 ± 0.01 μM) were evaluated <em>in vivo</em> against <em>Trypanosoma congolense</em>, the causative agent of <em>nagana</em>, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116979"},"PeriodicalIF":6.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors","authors":"Huaxuan Li ,&nbsp;Hong Yang ,&nbsp;Li Liu ,&nbsp;Jiahong Zheng ,&nbsp;Qiongyu Shi ,&nbsp;Bang Li ,&nbsp;Xingcan Wang ,&nbsp;Ying Zhang ,&nbsp;Ruilin Zhou ,&nbsp;Jian Zhang ,&nbsp;Zhong-Zhu Chen ,&nbsp;Chang-Yun Wang ,&nbsp;Yuanxiang Wang ,&nbsp;Xun Huang ,&nbsp;Zhiqing Liu","doi":"10.1016/j.ejmech.2024.116970","DOIUrl":"10.1016/j.ejmech.2024.116970","url":null,"abstract":"<div><div>The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound <strong>36</strong> exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound <strong>36</strong> potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound <strong>36</strong> had more favorable metabolic stability and aqueous solubility than JNJ64619178 (<strong>9</strong>). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that <strong>36</strong> is a highly potent and selective PRMT5 inhibitor worthy for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 116970"},"PeriodicalIF":6.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coumarin-Quinazolinone based photosensitizers: Mitochondria and endoplasmic reticulum targeting for enhanced phototherapy via different cell death pathways","authors":"Xuzi Zhao ,&nbsp;Ting Wang ,&nbsp;Fucheng Shang ,&nbsp;Jiangyu Yan ,&nbsp;Mingyan Jiang ,&nbsp;Xiaoyan Zou ,&nbsp;Guorui Li ,&nbsp;Zhibin Song ,&nbsp;Jing Huang","doi":"10.1016/j.ejmech.2024.116990","DOIUrl":"10.1016/j.ejmech.2024.116990","url":null,"abstract":"<div><div>Organelle-targeted photosensitizers (PSs) offer valuable tools for improving photodynamic therapy (PDT), yet systematic studies on how different organelles influence phototherapeutic outcomes are limited. In particular, the connection between organelle targeting and various modes of programmed cell death remains unclear. In this study, we developed a series of PSs using the Coumarin-Quinazolinone (<strong>CQ</strong>) scaffold, each designed to target different organelles, including the mitochondria, endoplasmic reticulum (ER), lysosome, and nucleolus. Our results show that their PDT performance is highly dependent on their localization, with phototoxic index (PI) ranging from 2 to 245. Notably, the mitochondria-targeted <strong>CQ-Mito</strong> and ER-targeted <strong>CQ-ER</strong> exhibited profound phototherapeutic performances, with PI of 167 and 245 respectively. Our further study reveals that <strong>CQ-Mito</strong> causes cell death by both apoptosis and ferroptosis, while <strong>CQ-ER</strong> primarily triggers ferroptosis. This study not only provides new agents for PDT but also offers insights into how organelle targeting influences cell death mechanisms, which can shed light on the design of PSs for controlled cell death.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116990"},"PeriodicalIF":6.0,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of membrane-targeting chalcone derivatives as antibacterial agents against multidrug-resistant bacteria","authors":"Siyu Yang ,&nbsp;Guoqing Miao ,&nbsp;Xinyu Wang ,&nbsp;Fen Zhou ,&nbsp;Ziheng Yuan ,&nbsp;Fuyao Wei ,&nbsp;Lusha Ji ,&nbsp;Xuekun Wang ,&nbsp;Gaopan Dong ,&nbsp;Yinhu Wang","doi":"10.1016/j.ejmech.2024.116969","DOIUrl":"10.1016/j.ejmech.2024.116969","url":null,"abstract":"<div><div>The striking rise of infections caused by multidrug-resistant pathogens has evolved as a serious threat to public health worldwide. To develop new antibacterials to combat multidrug-resistant bacteria, a novel class of amphiphilic chalcone derivatives serving as antimicrobial peptidomimetics was designed and synthesized. Among them, the most promising compound <strong>14b</strong> displayed broad-spectrum antimicrobial activity against both Gram-positive bacteria (MICs = 0.5–1 μg/mL) and Gram-negative bacteria (MICs = 1–32 μg/mL), low hemolytic activity, and good membrane selectivity. Moreover, compound <strong>14b</strong> exhibited rapid bactericidal action, a low probability of developing resistance, high proteolytic stability, and strong capabilities of inhibiting and destroying bacterial biofilms. Further mechanism investigations revealed that compound <strong>14b</strong> possessed strong membrane-disrupting abilities and could disintegrate the integrity of bacterial cell membranes by destroying transmembrane potential and enhancing membrane permeability, and causing the generation of intracellular ROS and the leakage of DNA and proteins, ultimately leading to bacterial death. More importantly, compound <strong>14b</strong> also showed excellent <em>in vivo</em> therapeutic potency in a mouse septicemia model infected by both Gram-positive and Gram-negative bacteria, indicating its potential to be an antibacterial agent to confront bacterial infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116969"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors (2019–2023)","authors":"Mu-Zi Nie ,&nbsp;Shuang-Shuang Zhang ,&nbsp;Shuang-Xi Gu ,&nbsp;Jiao Long ,&nbsp;Yuan-Yuan Zhu","doi":"10.1016/j.ejmech.2024.116973","DOIUrl":"10.1016/j.ejmech.2024.116973","url":null,"abstract":"<div><div>Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a vital cornerstone of highly active antiretroviral therapy (HAART) regimens, owing to their unique antiviral activity, low toxicity and high specificity. Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine and rilpivirine, have attracted extensive attention due to their high anti-HIV potency. However, rapid emergence of resistant mutations, suboptimal pharmacokinetics (PK), and toxicity remain significant challenges. Recent structural modifications of DAPY analogues have focused on improving resistance profiles, optimizing PK properties (such as half-life and bioavailability), diversifying core structures through scaffold hopping, refining side-chain structures to enhance activity and selectivity, and reducing toxicity and side effects. Moreover, developing new DAPY analogues with broad-spectrum antiviral activity has become a key research priority. This review provides a comprehensive overview of the evolution of DAPYs from 2019 to 2023, including scaffold hopping and structural modifications of the right wing, left wing, central pyrimidine core, and linker, affording valuable insights for the future development of effective HIV-1 inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116973"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trivalent oleanolic acid-glucose conjugates: Synthesis and efficacy against Influenza A virus","authors":"Ming Cai ,&nbsp;Yuan Zhang ,&nbsp;Jie Zhen ,&nbsp;Fan Yang,&nbsp;Xia Ou,&nbsp;Jihong Zhang,&nbsp;Fei Yu","doi":"10.1016/j.ejmech.2024.116977","DOIUrl":"10.1016/j.ejmech.2024.116977","url":null,"abstract":"<div><div>Influenza A virus (IAV) leads to significant morbidity and mortality due to the seasonal epidemics and spread. We have demonstrated that oleanolic acid (OA) C28 glucose conjugates and OA trimers are capable of effectively blocking the recognition and interaction between the influenza virus and host cells. In this study, a series of OA-glucose trimers were designed and synthesized through the CuAAC reaction. All trimers underwent screening for anti-IAV activities in vitro. Among these, compounds <strong>13a</strong> and <strong>13b</strong> showed inhibitory activity against the influenza virus, with IC₅₀ values of 0.68 μM and 0.47 μM, respectively, demonstrating greater potency than oseltamivir (IC₅₀ = 1.36 μM). Results from the time-of-addition experiment and hemagglutination inhibition assay suggest that these OA-glucose trimers may disrupt the recognition between the HA protein of IAV and sialic acid receptors on host cells, thus blocking viral entry. Furthermore, it was found that compound <strong>13b</strong> effectively inhibits IAV infection in BALB/c mice. This study has elucidated the structure-activity relationships of OA trimers against the influenza virus and highlighted the utility of multivalent OA conjugates for enhancing ligand-target interactions in anti-influenza virus drug design, laying a groundwork for future research into the antiviral applications of these natural products.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116977"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of quinazoline-benzothiazole derivatives as novel potent protease-activated receptor 4 antagonists with improved pharmacokinetics and low bleeding liability","authors":"Shanshan Li ,&nbsp;Shangde Liu ,&nbsp;Duo Yuan ,&nbsp;Renjie Liu ,&nbsp;Lifang Hu ,&nbsp;Xiong Zhu","doi":"10.1016/j.ejmech.2024.116980","DOIUrl":"10.1016/j.ejmech.2024.116980","url":null,"abstract":"<div><div>Protease-activated receptor 4 (PAR4) plays a critical role in the development of pathological thrombosis, and targeting PAR4 is considered a promising strategy for improving antiplatelet therapies. Here, we reported the design of a series of quinazoline-benzothiazole-based PAR4 antagonists using a scaffold-hopping strategy. Systematic structure-activity relationship exploration leads to the discovery of compounds <strong>20f</strong> and 2<strong>0g</strong>, which displayed optimal activity (<em>h</em>. PAR4-AP PRP IC₅₀ = 6.39 nM and 3.45 nM, respectively) on human platelets and high selectivity for PAR4. Both of them also showed excellent metabolic stability in human liver microsomes (compound <strong>20f</strong>, T_1/2 = 249.83 min, compound <strong>20g</strong>, T_1/2 = 282.60 min) and favourable PK profiles in rats (compound <strong>20f</strong>, T_1/2 = 5.16 h, <em>F</em> = 50.5 %, compound <strong>20g</strong>, T_1/2 = 7.05 h, <em>F</em> = 27.3 %). More importantly, neither compound prolonged the bleeding time in the mouse tail-cutting model (10 mg/kg, <em>p.o</em>.). These results suggest that these compounds have great potential for use in antiplatelet therapies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116980"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2","authors":"Kouki Shinohara ,&nbsp;Takuya Kobayakawa ,&nbsp;Kohei Tsuji ,&nbsp;Yuki Takamatsu ,&nbsp;Hiroaki Mitsuya ,&nbsp;Hirokazu Tamamura","doi":"10.1016/j.ejmech.2024.116963","DOIUrl":"10.1016/j.ejmech.2024.116963","url":null,"abstract":"<div><div>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M^pro) and a papain-like protease (PL^pro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL^pro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL^pro showed that GRL-0048 noncovalently interacts with PL^pro, and there is a newly identified binding pocket in PL^pro. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds <strong>1</strong>, <strong>2b</strong>, and <strong>3h</strong>, that have more potent inhibitory activity than GRL-0048.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116963"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects","authors":"Jan Konecny ,&nbsp;Anna Misiachna ,&nbsp;Marketa Chvojkova ,&nbsp;Lenka Kleteckova ,&nbsp;Marharyta Kolcheva ,&nbsp;Martin Novak ,&nbsp;Lukas Prchal ,&nbsp;Marek Ladislav ,&nbsp;Katarina Hemelikova ,&nbsp;Jakub Netolicky ,&nbsp;Martina Hrabinova ,&nbsp;Tereza Kobrlova ,&nbsp;Jana Zdarova Karasova ,&nbsp;Jaroslav Pejchal ,&nbsp;Jakub Fibigar ,&nbsp;Zbynek Vecera ,&nbsp;Tomas Kucera ,&nbsp;Pavla Jendelova ,&nbsp;Petra Zahumenska ,&nbsp;Emily Langore ,&nbsp;Martin Horak","doi":"10.1016/j.ejmech.2024.116981","DOIUrl":"10.1016/j.ejmech.2024.116981","url":null,"abstract":"<div><div>We aimed to prepare novel dibenzo [<em>a,d</em>][7]annulen derivatives that act on <em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our <em>in silico</em> analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds <strong>3l</strong> and <strong>6f</strong> to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, <strong>6f</strong> showed high relative inhibition (∼90 % for GluN1/GluN2A), while <strong>3l</strong> showed moderate inhibition (∼50 %). An <em>in vivo</em> toxicity study determined that compounds <strong>3l</strong> and <strong>6f</strong> were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound <strong>3l</strong> at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [<em>a,d</em>][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116981"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, in vitro and in vivo biological evaluation of novel dual compounds targeting both acetylcholinesterase and serotonergic 5-HT4 receptors with potential interest in the treatment of Alzheimer's disease","authors":"Christophe Rochais ,&nbsp;Cédric Lecoutey ,&nbsp;Julien Lalut ,&nbsp;Audrey Davis ,&nbsp;Emilie Duval ,&nbsp;Florence Gaven ,&nbsp;Stacy Largillière ,&nbsp;Gérald Née ,&nbsp;Sophie Corvaisier ,&nbsp;Jana Sopkova de Oliveira Santos ,&nbsp;Marc Since ,&nbsp;Thomas Freret ,&nbsp;Romain Legrand ,&nbsp;Noëlle Callizot ,&nbsp;Sylvie Claeysen ,&nbsp;Michel Boulouard ,&nbsp;Patrick Dallemagne","doi":"10.1016/j.ejmech.2024.116975","DOIUrl":"10.1016/j.ejmech.2024.116975","url":null,"abstract":"<div><div>In this work, we exemplified the “copride” family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT₄ receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride. In this respect, the replacement of the methoxy group of the latter with a deuterated one led to deudonecopride. On the other hand, the replacement of the chlorine atom of donecopride by various halogen atoms was of particular interest, among which fluorine led to a potent analog, we called flucopride. The latter exhibited promising <em>in vitro</em> activities associated to excellent drugability parameters. Flucopride was consequently involved in <em>in vivo</em> studies such as a scopolamine-induced deficit model of working memory and in a novel object recognition test. Through these evaluations, flucopride demonstrated both its antiamnesiant and promnesiant capacities, which could make it a potential preclinical drug candidate for the treatment of Alzheimer's disease.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"280 ","pages":"Article 116975"},"PeriodicalIF":6.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}