Archiv der Pharmazie最新文献

{"title":"New benzimidazole–indole–amide derivatives as potent α-glucosidase and acetylcholinesterase inhibitors","authors":"Narges Naimi,&nbsp;Somaye Karimian,&nbsp;Navid Dastyafteh,&nbsp;Mild Noori,&nbsp;Maryam Mohammadi-Khanaposhtani,&nbsp;Armin Dadgar,&nbsp;Bagher Larijani,&nbsp;Vahid Lotfi,&nbsp;İlhami Çelik,&nbsp;Aydın Aktaş,&nbsp;Nastaran Sadeghian,&nbsp;Parham Taslimi,&nbsp;Mohammad Mahdavi","doi":"10.1002/ardp.202400354","DOIUrl":"10.1002/ardp.202400354","url":null,"abstract":"<p>New derivatives <b>6a–m</b> with benzimidazole–indole–amide scaffold were developed, synthesized, and assessed for potential inhibitory effects on α-glucosidase and acetylcholinesterase (AChE). These compounds were synthesized by various amine derivatives. With the exception of two compounds, the α-glucosidase inhibitory activities of the title derivatives were more than that of the positive control acarbose. Moreover, the anti-AChE activity of these compounds, with the exception of one compound, was better than that of tacrine (standard inhibitor). The most potent compound against α-glucosidase was 3-methylphenyl derivative <b>6i</b> and the most potent compound against AChE was 3,4-dimethoxyphenethyl derivative <b>6m</b>. All the synthesized compounds were placed in the active sites of α-glucosidase and AChE by in silico docking method and the obtained binding energies were approximately in agreement with the in vitro observed data. Interaction modes of the most potent compounds <b>6i</b> and <b>6m</b> demonstrated that these compounds interacted with important residues of their target enzymes. Molecular dynamics simulation was conducted specifically on compound <b>6i</b> in complex with α-glucosidase to obtain deeper insights into the behavior of this molecule. Furthermore, in silico pharmacokinetic and toxicity studies on the most potent compound predicted that these compounds have good profiles in terms of oral absorption and toxicity.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of xanthone-based nitric oxide donors targeting biofilm clearance","authors":"Qun Tang,&nbsp;Wenchong Ye,&nbsp;Kasemsiri Chandarajoti,&nbsp;Rile Ge,&nbsp;Sai Lv,&nbsp;Keyu Zhang,&nbsp;Xiangan Han,&nbsp;Chunmei Wang,&nbsp;Han Bai,&nbsp;Xiaoyang Wang,&nbsp;Wen Zhou","doi":"10.1002/ardp.202400793","DOIUrl":"10.1002/ardp.202400793","url":null,"abstract":"<p>Bacteria biofilm infection seriously challenges clinical drug therapy. Nitric oxide (NO) was reported to disperse biofilm, eliminate bacteria resistance and kill bacteria. In this study, on the basis of membrane targeting of α-mangostin (α-MG) and the dispersion effect of NO on bacteria biofilms, we designed and synthesized 30 NO donors that α-MG was conjugated with a nitrobenzene or a nitrate and other four representative reference derivatives. Compound <b>23</b> with 2-chloro-4-nitrobenzoyl introduced in the position C6 of α-MG exhibited the prominent ability to eradicate <i>Staphylococcous aureus</i> biofilm, and a more long-lasting and stable bactericidal effect in vitro, and lower hemolytic activity over α-MG. Moreover, a mouse wound model infected by <i>S. aureus</i> biofilm supported the in vivo reduced bacterial burden closely associated with the NO release from compound <b>23</b> that exerted a dispersing effect on biofilms. Therefore, our design strategy can provide a promising and effective solution to intervene in biofilm infection with high specificity.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depsides from Origanum dictamnus and Satureja pilosa as selective inhibitors of carbonic anhydrases: Isolation, structure elucidation, X-ray crystallography","authors":"Charikleia Paloukopoulou,&nbsp;Ogouschan Salim Ntagli,&nbsp;Luca Gherardi,&nbsp;Virginia Dourdouni,&nbsp;Glykeria Filippou,&nbsp;Vincenzo Alterio,&nbsp;Simone Giovannuzzi,&nbsp;Maria Luisa Massardi,&nbsp;Giuseppina De Simone,&nbsp;Roberto Ronca,&nbsp;Claudiu T. Supuran,&nbsp;Gennaro Pescitelli,&nbsp;Anastasia Karioti","doi":"10.1002/ardp.202400823","DOIUrl":"10.1002/ardp.202400823","url":null,"abstract":"<p>In this study, four depsides were isolated from <i>Origanum dictamnus</i> L. and <i>Satureja pilosa</i> <span>Velen.</span> medicinal plants and their structures were assessed by means of one-dimensional (1D)- and two-dimensional (2D)-nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses. The compound <b>1</b>, herein reported for the first time, salvianolic acid P <b>2</b>, clinopodic acid I <b>3</b>, and clinopodic acid O <b>4</b> were all profiled in vitro on a panel of human (h) expressed carbonic anhydrases (CAs; EC 4.2.1.1) and preferential inhibition for the tumor-associated human carbonic anhydrase (hCA) IX and hCA XII over the constitutively expressed hCA I and hCA II isoforms was observed. X-ray crystallography allowed us to assess the binding mode of salvianolic acid P <b>2</b> to hCA II. The compounds exhibited significant cytotoxic effects on the human triple-negative breast cancer cell line MDA-MB-231, suggesting that this class of depsides are promising molecules for future investigation.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-methyl-2-carboxamidepyrrole-based novel dual mPGES-1/sEH inhibitors as promising anticancer candidates","authors":"Ester Colarusso,&nbsp;Gianluigi Lauro,&nbsp;Marianna Potenza,&nbsp;Paola Galatello,&nbsp;Maria Luisa d'Aulisio Garigliota,&nbsp;Maria Grazia Ferraro,&nbsp;Marialuisa Piccolo,&nbsp;Maria Giovanna Chini,&nbsp;Carlo Irace,&nbsp;Pietro Campiglia,&nbsp;Robert Klaus Hoffstetter,&nbsp;Oliver Werz,&nbsp;Anna Ramunno,&nbsp;Giuseppe Bifulco","doi":"10.1002/ardp.202400708","DOIUrl":"10.1002/ardp.202400708","url":null,"abstract":"<p>Inhibiting microsomal prostaglandin E₂ synthase-1 (mPGES-1), an inducible enzyme involved in prostaglandin E₂ (PGE₂) biosynthesis and tumor microenvironment (TME) homeostasis, is a valuable strategy for treating inflammation and cancer. In this work, 5-methylcarboxamidepyrrole-based molecules were designed and synthesized as new compounds targeting mPGES-1. Remarkably, compounds <b>1f</b>, <b>2b</b>, <b>2c</b>, and <b>2d</b> were able to significantly reduce the activity of the isolated enzyme, showing IC₅₀ values in the low micromolar range. With the aim of further profiling the synthesized molecules, their ability to interfere with the activity of soluble epoxide hydrolase (sEH), whose inhibition blocks the loss of the anti-inflammatory mediators epoxyeicosatrienoic acids (EETs or epoxyicosatrienoic acids), was investigated in silico and by employing specific biological assays. Among the set of tested compounds, <b>1f</b>, <b>2b</b>, <b>2c</b>, and <b>2d</b> emerged as mPGES-1/sEH dual inhibitors. Moreover, given that overexpression of mPGES-1 has been observed in many human tumors, we finally explored the biological effect of our compounds in an in vitro model of human colorectal cancer (CRC). The obtained outcomes pave the way for future investigation to optimize and further characterize anticancer pharmacological profile of the carboxamidepyrrole-based molecules.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring aliphatic sulfonamides as multiclass inhibitors of the carbonic anhydrases from the pathogen bacterium Vibrio cholerae","authors":"Niccolò Paoletti,&nbsp;Simone Giovannuzzi,&nbsp;Alessandro Bonardi,&nbsp;Viviana De Luca,&nbsp;Clemente Capasso,&nbsp;Alessio Nocentini,&nbsp;Paola Gratteri,&nbsp;Claudiu T. Supuran","doi":"10.1002/ardp.202400814","DOIUrl":"10.1002/ardp.202400814","url":null,"abstract":"<p>This study investigates aliphatic sulfonamide derivatives as inhibitors of the α-, β-, and γ-class carbonic anhydrase (CA) isoforms from <i>Vibrio cholerae</i> (VchCAs). A series of 26 compounds bearing a triazole linker and urea- or ether-based tails were described and evaluated for their inhibitory action using a stopped-flow CO₂ hydrase technique. These inhibitors demonstrated a preferential efficacy against VchCAβ. Specifically, the ureido derivatives showed the highest inhibitory potency with inhibition constants (<i>K</i>_Is) in the submicromolar range (0.67–0.93 µM). Selectivity indices were calculated to assess the selective inhibition of VchCAβ over human CA I and II, as well as other VchCA isozymes. Urea-linked compounds demonstrated a significant 25- to 125-fold selectivity for VchCAβ over hCAs and 14- to 26-fold over other VchCAs. Molecular modeling elucidated the interactions contributing to the efficacy and selectivity of aliphatic sulfonamides as VchCA inhibitors, aligning with and reinforcing the experimental results. The latter suggests that aliphatic sulfonamides could serve as valid targeted therapeutics to treat <i>V. cholerae</i> infections.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400814","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New 7-hydroxycoumarin acetamide derivatives as human carbonic anhydrase IX and XII inhibitors: Design, synthesis, biological evaluation and molecular docking studies","authors":"Sarvan Maddipatla,&nbsp;Bulti Bakchi,&nbsp;Mayura Anil Shinde,&nbsp;Alessandro Bonardi,&nbsp;Preethi K. Raman,&nbsp;Harshada Anil Bhalerao,&nbsp;Anuradha Singampalli,&nbsp;Srinivas Nanduri,&nbsp;Chandraiah Godugu,&nbsp;Rajesh Sonti,&nbsp;Claudiu T. Supuran,&nbsp;Venkata Madhavi Yaddanapudi","doi":"10.1002/ardp.202400482","DOIUrl":"10.1002/ardp.202400482","url":null,"abstract":"<p>Carbonic anhydrases (CAs) are crucial in regulating various physiological processes in the body. The overexpression of isoforms human carbonic anhydrases (hCA) IX and hCA XII is linked to tumour progression. The selective inhibition of CA IX and CA XII isoforms can result in the development of better cancer treatment strategies. The tail approach based on coumarin derivatives was known for selective inhibition of isoforms IX and XII. This study explores the potential of coumarin derivatives (<b>7a–k</b>, <b>8a–s</b> and <b>9a–g</b>) as selective hCA IX and hCA XII inhibitors. The synthesised derivatives exhibited potent and selective inhibition towards hCA IX and XII, with <i>K</i>_i values in the range of 0.58‒3.33 µM and 0.48‒2.59 µM, respectively. The oxime ether derivative <b>7d</b> was found to be the most potent one against hCA IX, with a <i>K</i>_i value of 0.58 µM, and phenyl hydrazine derivative <b>8a</b>, with a <i>K</i>_i value of 0.48 µM against hCA XII, was the most potent one among the synthesised molecules. The potent isoform-specific carbonic anhydrase IX and XII inhibition suggests that <b>7d</b> and <b>8a</b> can be taken further towards the development of potent anticancer agents.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease","authors":"Galina F. Makhaeva,&nbsp;Maria V. Grishchenko,&nbsp;Nadezhda V. Kovaleva,&nbsp;Natalia P. Boltneva,&nbsp;Elena V. Rudakova,&nbsp;Tatiana Y. Astakhova,&nbsp;Elena N. Timokhina,&nbsp;Pavel G. Pronkin,&nbsp;Sofya V. Lushchekina,&nbsp;Olga G. Khudina,&nbsp;Ekaterina F. Zhilina,&nbsp;Evgeny V. Shchegolkov,&nbsp;Maria A. Lapshina,&nbsp;Elena S. Dubrovskaya,&nbsp;Eugene V. Radchenko,&nbsp;Vladimir A. Palyulin,&nbsp;Yanina V. Burgart,&nbsp;Victor I. Saloutin,&nbsp;Valery N. Charushin,&nbsp;Rudy J. Richardson","doi":"10.1002/ardp.202400819","DOIUrl":"10.1002/ardp.202400819","url":null,"abstract":"<p>New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC₅₀: AChE, 0.265−4.24 μM; BChE, 0.01−0.64 μM) but poor activity against off-target carboxylesterase (CES). Specifically, conjugates with a (CH₂)₈ spacer showed the highest AChE and BChE inhibition: 3–16 times more effective than amiridine. Salicylamides <b>7b</b> and <b>7c</b> had the maximum BChE/AChE selectivity ratios: 193 and 138, respectively. Conjugates were mixed-type reversible inhibitors of both cholinesterases and displaced propidium from the AChE peripheral anionic site (PAS) at the level of donepezil. All conjugates inhibited Aβ₄₂ self-aggregation in the thioflavin test; inhibition increased with spacer elongation, being greatest for (CH₂)₈. The results agreed with molecular docking to AChE, BChE, and Aβ₄₂. Conjugates exhibited high 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)^•+-scavenging activity comparable to the standard antioxidant Trolox, and they showed the ability to bind Cu²⁺, Fe²⁺, and Zn²⁺. Conjugates had favorable predicted intestinal absorption and blood–brain barrier permeability. Altogether, the results indicate that the new conjugates possess potential for further development as multifunctional anti-AD drug candidates.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400819","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information: Arch Pharm (1/2025)","authors":"","doi":"10.1002/ardp.202570001","DOIUrl":"https://doi.org/10.1002/ardp.202570001","url":null,"abstract":"","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202570001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress on the pathogenesis of psoriasis and its small molecule inhibitors","authors":"Lulu Xia,&nbsp;Hongxin Li,&nbsp;Li Long,&nbsp;Wei Ruan,&nbsp;Jiajia Ma,&nbsp;Shan Xu,&nbsp;Dan Qiao","doi":"10.1002/ardp.202400621","DOIUrl":"10.1002/ardp.202400621","url":null,"abstract":"<p>Psoriasis is a prevalent chronic systemic immune disease characterized by T-cellmediated hyperproliferation of keratinized cells. Among its various manifestations, plaque-type psoriasis is the most common. Treatment options for psoriasis encompass topical medications, biological therapies, phototherapy techniques, and others. However, traditional treatments are associated with numerous side effects. In contrast, targeted therapy has garnered increasing attention due to its high selectivity, strong safety profile, and favorable therapeutic outcomes. Patients with psoriasis lesions exhibit elevated levels of proinflammatory cytokines compared with the general population. These proinflammatory cytokines have been implicated in mediating psoriasis pathogenesis by inducing keratinocyte proliferation through multiple signaling pathways within the body. This study will delve into the Janus kinase-signal transducers and activators of transcription, phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB, also known as AKT), and nuclear factor Kappa-light-chain-enhancer of activated B cells signaling pathways to elucidate their roles in mediating psoriasis pathogenesis. In addition, we will summarize potential targets relevant to the treatment of psoriasis and discuss the design and activity assessment of their inhibitors. It also provides new insights for further in-depth study of psoriasis and development of novel molecularly targeted inhibitors.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the sulfaguanidine molecular scaffold in drug design and development","authors":"Hamada S. Abulkhair","doi":"10.1002/ardp.202400802","DOIUrl":"10.1002/ardp.202400802","url":null,"abstract":"<p>Developing new molecular entities is one of the most emerging research areas in the field of Medicinal Chemistry. Over the past few years, rigorous research has been conducted on sulfaguanidine-linked synthetic molecules because of their promising potential in several biological activities. Sulfaguanidine has been actively incorporated in the design of anticancer, antimicrobial, antidiabetic, antiparkinsonian, anti-inflammatory, and antiviral candidates. The construction of these effective candidates has adopted many chemical approaches. A number of the prepared compounds displayed promising results that merit further investigations for the development of new medications. This review summarizes the different chemical strategies and the reported activities for sulfaguanidine-linked synthetic molecules throughout 2020–2024.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 1","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}