European Journal of Medicinal Chemistry Reports最新文献

{"title":"Anticancer α-, γ-, and δ-carboline derivatives: structures, mechanisms of action, and SARs","authors":"Jingliang Cui,&nbsp;Wanru Gao,&nbsp;Ziwei Liu,&nbsp;Shuang Cao,&nbsp;Sihui Long","doi":"10.1016/j.ejmcr.2024.100221","DOIUrl":"10.1016/j.ejmcr.2024.100221","url":null,"abstract":"<div><div>Carboline consists of a pyridine ring fused with an indole skeleton, and it serves as a potential drug scaffold. Depending on the relative position of the pyridine N to the indole N, carbolines can be categorized into <em>α-, β-, γ-,</em> and <em>δ</em>-subfamilies. They have diverse pharmacological activities, such as anticancer, antimalaria, antibacterial, antifungal, anti-Alzheimer's disease, etc. Among them, <em>β</em>-carbolines are the most widely studied and are also well reviewed. Herein, we review the anticancer activity of <em>α-, γ-,</em> and <em>δ</em>-carboline natural products and their synthetic derivatives, as they provide new inroads for cancer therapy. Particularly, we highlight the new derivatives of <em>α-, γ-,</em> and <em>δ</em>-carboline with anticancer activity, and their anticancer mechanisms, as well as structure-activity relationship. Meanwhile, we propose strategies for the development of new <em>α-</em>, <em>γ-</em>, and <em>δ</em>-carboline derivatives for cancer therapy.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100221"},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review on progress of thiazole derivatives as potential anti-inflammatory agents","authors":"Kereyagalahally H. Narasimhamurthy ,&nbsp;Toreshettahally R. Swaroop ,&nbsp;Kanchugarakoppal S. Rangappa","doi":"10.1016/j.ejmcr.2024.100225","DOIUrl":"10.1016/j.ejmcr.2024.100225","url":null,"abstract":"<div><div>Inflammation is a body response against infection that activates other biological components that include various cytokines, chemokines and other biological compounds that trigger body response against pathological activities. The Arachidonic acid pathway is involved in the inflammation that is connected with lipoxygenase (LOX) and cyclooxygenase (COX) enzymes. The importance of the isoforms of LOX and COX in inflammation is well studied. At the cellular level, some of the thiazole derivatives showed potent anti-inflammatory activities especially to block LOX5 and COX2 in the inflammation. These factors include both acute and chronic inflammation in various tissues like the heart, kidney, pancreas, brain, intestine, lungs and other organs as well that lead to the damage of the organs or cells. Whether it's the infectious or non-infectious response it will further activate some of the downstream signaling pathways like lipoxygenase, cyclooxygenase, cytochrome 450, JAK-STAT, MAPK, JNK, TNF-α, Nfr2, and many more pathways that lead to activation of another chronic disease in the body. In this review, we will concentrate on thiazole molecules that serve as anti-inflammatory responses to both acute and chronic inflammation. Further, we discussed the evidence that correlates the possible connection with LOX and COX enzymes in the inflammatory pathways and their blocking ability especially through thiazole derivatives has been discussed in this present review. The current assessment is the best part of the present consequence of thiazole derivatives on anti-inflammatory studies, covering articles published from 1973 to 2023.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100225"},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel favipiravir derivatives with improved pharmacokinetic properties as anti-SFTSV agents","authors":"Xiaomeng He ,&nbsp;Fan Wu ,&nbsp;Wei Li ,&nbsp;Runze Zhang ,&nbsp;Ruiyang Sun ,&nbsp;Zhihong Hu ,&nbsp;Wu Zhong ,&nbsp;Manli Wang","doi":"10.1016/j.ejmcr.2024.100226","DOIUrl":"10.1016/j.ejmcr.2024.100226","url":null,"abstract":"<div><div>Favipiravir is a nucleobase analogue that exhibits antiviral activities against a variety of RNA viruses. Due to the lack of antivirals to combat SFTS, an emerging tickborne epidemic caused by a RNA virus belonging to the Phenuividae family within Bunyavirales, Favipiravir has been put brand new attention as optimal SFTS clinical candidate. We here disclose chemical synthesis of novel derivatives of Favipiravir. All derivatives showed favorable inhibitory effect on SFTSV replication <em>in vitro</em>. The 50 % effective concentration (EC₅₀) of the most active compound <strong>H3</strong> was 12.06 μM, better than that of Favipiravir (15.51 μM). Most importantly, compared with the clinical candidate Favipiravir, pharmacokinetic studies conducted on rats demonstrated enhanced pharmacokinetic properties for <strong>H2</strong> and <strong>H3</strong> including parameters of T_1/2, C_max and AUC. These combined attributes identified novel promising drug candidates for the treatment of SFTSV infection.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100226"},"PeriodicalIF":0.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Truncated NPY-based NPY(Y1)R-specific radiopeptides: Improved in vivo PET tumor imaging by application of peptidase inhibitors","authors":"Benedikt Judmann ,&nbsp;Nils F. Baier ,&nbsp;Henning Rudolf ,&nbsp;Güllü Davarci ,&nbsp;Björn Wängler ,&nbsp;Ralf Schirrmacher ,&nbsp;Gert Fricker ,&nbsp;Carmen Wängler","doi":"10.1016/j.ejmcr.2024.100223","DOIUrl":"10.1016/j.ejmcr.2024.100223","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The neuropeptide Y receptor subtype 1 (NPY(Y&lt;sub&gt;1&lt;/sub&gt;)R) exhibits high expression rates on human breast cancer and is therefore an important target structure for the sensitive and specific visualization and characterization of the disease by Positron Emission Tomography (PET). However, imaging of this receptor type has been of limited success so far due to the low stability of peptide-based NPY-derived NPY(Y&lt;sub&gt;1&lt;/sub&gt;)R-specific radiotracer candidates due to &lt;em&gt;in vivo&lt;/em&gt; degradation. Given the challenges in stabilizing these agents, our study sought to explore whether the stability of NPY(Y&lt;sub&gt;1&lt;/sub&gt;)R-specific radiopeptides could be enhanced. We aimed to achieve this by either modifying the peptide structure with various molecular scaffolds or by applying peptidase inhibitors. This evaluation aimed to identify the optimal approach for achieving effective NPY(Y&lt;sub&gt;1&lt;/sub&gt;)R-specific imaging in the following. To validate our approach, we systematically investigated four new truncated &lt;sup&gt;68&lt;/sup&gt;Ga-labeled analogs of NPY and the reference compound [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-[Lys&lt;sup&gt;4&lt;/sup&gt;(N&lt;sub&gt;ε&lt;/sub&gt;-DOTA)]BVD15, bearing different molecular scaffolds such as a DOTA or NODA-GA chelator, a 4-APipAc linker, a Bip unit, and an &lt;em&gt;N&lt;/em&gt;-terminal Lys(lauryl) group. The four new radiotracers as well as the reference compound were obtained in high chemical and radiochemical yields with molar activities of 33–39 GBq/μmol. The radiopeptides exhibited varying log&lt;sub&gt;&lt;em&gt;D&lt;/em&gt;7.4&lt;/sub&gt; values, ranging from −3.37 ± 0.09 to +0.35 ± 0.11, and showed different levels of stability in human serum and liver microsomes, depending on their molecular structure. Subsequently, the influence of the peptidase inhibitors actinonin, phosphoramidon, captopril and E−64 on the &lt;em&gt;in vitro&lt;/em&gt; stability of the radiotracers was investigated. In these studies, only actinonin demonstrated a positive effect on the stability of all radiopeptides. In contrast, phosphoramidon yielded variable results, and neither captopril nor E−64 showed a significant stabilizing effect.&lt;/div&gt;&lt;div&gt;Consequently, the effect of actinonin administration on the &lt;em&gt;in vivo&lt;/em&gt; PET/CT imaging results of the most promising ligand [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-[Lys&lt;sup&gt;4&lt;/sup&gt;(N&lt;sub&gt;ε&lt;/sub&gt;-NODA-GA)]BVD15 ([&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-&lt;strong&gt;2&lt;/strong&gt;) was investigated in a T47D tumor-bearing xenograft mouse model, followed by &lt;em&gt;ex vivo&lt;/em&gt; biodistribution studies. In these experiments, the administration of 250 μg actinonin resulted in a significantly increased uptake of [&lt;sup&gt;68&lt;/sup&gt;Ga]Ga-&lt;strong&gt;2&lt;/strong&gt; in the T47D tumor (5.9 ± 1.0 % ID/g (with actinonin) instead of 3.1 ± 0.9 % ID/g (without actinonin) at 2h p.i.), and an increase in tumor-to-muscle ratios from 1.8 to 4.0 upon co-administration of the inhibitor.&lt;/div&gt;&lt;div&gt;The results impressively demonstrate the positive influence of actinonin on the &lt;em&gt;in vivo&lt;/em&gt; stability of the NPY(Y&lt;sub&gt;1&lt;/sub&gt;)R-specific radiopeptide [&lt;sup&gt;68&lt;/sup&gt;","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100223"},"PeriodicalIF":0.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer effect of new cyclocoumarol derivatives","authors":"Racha Karaky ,&nbsp;Joumana Al-Akhdar ,&nbsp;Fatima Saab ,&nbsp;Batoul Rostom ,&nbsp;Wassim Shebaby ,&nbsp;Mohamed Mroueh ,&nbsp;Mona Diab-Assaf ,&nbsp;Issam Kassab ,&nbsp;Maité Sylla-Iyarreta Veitia","doi":"10.1016/j.ejmcr.2024.100220","DOIUrl":"10.1016/j.ejmcr.2024.100220","url":null,"abstract":"<div><div>Coumarins have demonstrated a broad spectrum of pharmacological activities, including significant anticancer properties. Recently, a series of cyclocoumarol derivatives, a pyranocoumarin known for its anticoagulant and anti-inflammatory effects, have been synthesized and shown to have a selective inhibitory effect on cyclooxygenase-2 (COX-2). In this study, we evaluated the anticancer effects of these cyclocoumarol derivatives for the first time. We tested their antiproliferative effects on several human cancer cell lines, including MDAMB231, A549, MCF7, SF268, HCT116, HeLa, and Jurkat. The MTT assay revealed that the methylated cyclocoumarol derivative, 2-methoxy-2-methyl-(1-(p-tolyl))-3,4-dihydropyrano [3,2-c] chromen-5(2H)-one, <strong>5b</strong> exhibited the most potent antiproliferative activity, particularly against MDAMB231 cells. Further investigations demonstrated that <strong>5b</strong> induced apoptosis in MDAMB231 cells via the mitochondrial pathway, as indicated by increased Bax and decreased Bcl2 levels, along with caspase-3 activation and PARP cleavage. Additionally, compound <strong>5b</strong> significantly inhibited the clonogenic potential of MCF7 cells and reduced the migration capacity of MDAMB231, SF268, and A549 cells. These findings suggest that <strong>5b</strong> is a promising lead compound for developing new anticancer agents, with the potential for chemical optimization to enhance its efficacy.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100220"},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progression in nano-botanical oral hygiene solutions: The Dawn of biomimetic nanomaterials","authors":"Aqsa Arif ,&nbsp;Muhammad Sharif Khar ,&nbsp;Nariman Shahid ,&nbsp;Waqar Aman ,&nbsp;Joham Javed ,&nbsp;Amina Rubab ,&nbsp;Mashal Nayab ,&nbsp;khadija mastoor ,&nbsp;Rabia Arshad ,&nbsp;Abbas Rahdar ,&nbsp;Sonia Fathi-karkan ,&nbsp;Zelal Kharaba ,&nbsp;Sadanand Pandey","doi":"10.1016/j.ejmcr.2024.100219","DOIUrl":"10.1016/j.ejmcr.2024.100219","url":null,"abstract":"<div><div>Pathogenic bacteria consistently pose significant challenges within the oral mucosal environment by altering bioflora, biofilm development, and enamel demineralization, thus leading to extensive clinical resources for treatment. This review aims to gather suitable and novel information in terms of providing advanced bio-inspired therapeutic facilities to alleviate the burden of treatment on both the patient and medical infrastructure. Botanical nanoparticle-based mouthwashes have been synthesized using mostly green synthesis technology. Botanical nanoformulations-based mouthwashes are efficient for maintaining microbial flora and mimicking natural extracellular matrix (ECM) components. Furthermore, dental caries can also be treated by these nanoparticles through the promotion of enamel remineralization and bacterial growth suppression. These nature-inspired oral rinses/mouthwashes confer significant advantages relative to their synthetic counterparts, particularly in terms of safety, efficacy, and formulation simplicity. The potential applications of these bioinspired nanomaterials extend beyond wound healing and dental infection management, heralding a promising frontier in oral health restoration. The diversified range of these nanomaterials, from Propolis, Miswak, and Chitosan nanoparticles (NPs) to pomegranate extract and <em>Matricaria chamomilla L.</em> extract-based mouthwashes, introduces an exciting new dimension to oral care.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100219"},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semisynthesis: Bridging natural products and novel anticancer therapies","authors":"Bharat Goel ,&nbsp;Shreyans K. Jain","doi":"10.1016/j.ejmcr.2024.100218","DOIUrl":"10.1016/j.ejmcr.2024.100218","url":null,"abstract":"<div><div>Natural products (NPs) have played a central role in drug discovery particularly in therapeutic areas like oncology, and infectious diseases. Despite their pharmacological potential, natural products present some significant challenges for therapeutic applications, such as toxicity, pharmacokinetic characteristics, supply problems, and drug resistance. Some of these issues have been solved by semisynthetic derivatives of natural products, and many semisynthetic drugs have been developed and approved for clinical use. Repeatedly, it has been observed that outcomes of semisynthetic modifications of natural products retain the medicinal activity of the parent compound while altering other characteristics such as toxicity and oral bioavailability, escalating their momentum of reaching the market. This review describes NP-derived semisynthetic anticancer drugs approved from 1981 to 2023. The review also confers the advantages of semisynthetic modifications of natural products, including supply fulfillment, improved pharmacokinetics (increased bioavailability, plasma half-life, etc.), improved solubility and lipophilicity, reduced toxicity, enhanced selectivity, and reduced resistance.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of N-heterocyclic drugs, acids, phenols, and thiols via Tailor−made Self−immolative linkers","authors":"Vahid Barati ,&nbsp;Anna Hruzíková ,&nbsp;Eliška Procházková ,&nbsp;Martin Zavřel ,&nbsp;Jaroslav Kozák ,&nbsp;Jana Trylčová ,&nbsp;Dominik Rejman ,&nbsp;Jan Weber ,&nbsp;Kateřina Bogdanová ,&nbsp;Milan Kolář ,&nbsp;Ondřej Baszczyňski","doi":"10.1016/j.ejmcr.2024.100216","DOIUrl":"10.1016/j.ejmcr.2024.100216","url":null,"abstract":"<div><div>Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by ³¹P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B <em>in vitro</em>. Select prodrugs, including zidovudine prodrug <strong>33</strong>, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100216"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review","authors":"Muhammad Salman Hameed ,&nbsp;Hongxuan Cao ,&nbsp;Li Guo ,&nbsp;Lei Zeng ,&nbsp;Yanliang Ren","doi":"10.1016/j.ejmcr.2024.100217","DOIUrl":"10.1016/j.ejmcr.2024.100217","url":null,"abstract":"<div><div>Recent progress in the realm of covalent inhibitors and covalent drugs, placing a distinct emphasis on precisely defining the scope and outlining key objectives. The scope of this review encompasses a broad examination of various classes of covalent inhibitors and drugs, with a focus on their mechanisms, applications, and limitations. Specifically, we discuss the chemical principles underlying covalent interactions in drug design and delve into the structural features that render these compounds effective in their respective targets. Our objectives include summarizing recent research progress in the development and application of covalent inhibitors and drugs, identifying key challenges faced by researchers and clinicians, and proposing future directions for advancing the field. By synthesizing current knowledge and addressing emerging trends, this review aims to contribute to a deeper understanding of covalent inhibitors and drugs and to inspire further research efforts towards their development and optimization.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100217"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzylhydroxamic acids as inhibitors of insulin regulated aminopeptidase (IRAP)","authors":"Julia Beveridge ,&nbsp;Marcus Söderström ,&nbsp;Rubén Prieto-Díaz ,&nbsp;Hugo Gutierrez-de-Teran ,&nbsp;Luke R. Odell ,&nbsp;Mathias Hallberg ,&nbsp;Mats Larhed ,&nbsp;Johan Gising","doi":"10.1016/j.ejmcr.2024.100215","DOIUrl":"10.1016/j.ejmcr.2024.100215","url":null,"abstract":"<div><div>With the objective of finding new classes of cognitive enhancers with potential for the treatment of neurodegenerative disorders, such as Alzheimer's disease, small molecule inhibitors of insulin-regulated aminopeptidase (IRAP) were designed and synthesized. IRAP is a member of the M1 family of zinc aminopeptidases and is abundantly expressed in areas of the brain associated with cognition, such as the amygdala, hippocampus and cerebral cortex. IRAP inhibitors were previously shown to enhance memory and learning in animal models. A comprehensive high throughput screening of 400,000 small molecules from the European Lead Factory library provided a series of 50 promising compounds in a qualified hit list (QHL). More than 30 IRAP inhibitors with an IC₅₀ below 3.5 μM were identified. Herein, selected compounds from this QHL were assayed for solubility and permeability. Most of the selected compounds displayed good solubility, but further permeability studies on the best compounds revealed low blood brain barrier (BBB) permeability and high efflux in cells overexpressing P-gp pumps, rendering them less promising as starting points in drug discovery processes. Two compounds from the QHL were prioritized for further structural optimization; the pyridyl-substituted isoxazole <strong>1a</strong> (<strong>QHL27</strong>) and the benzylhydroxamic acid derivative <strong>1b</strong> (<strong>QHL1</strong>), both demonstrating fair BBB permeability and no indication of efflux. While our attempts to improve the isoxazole derivative <strong>1a</strong> were not fruitful, a structural modification of <strong>1b</strong> to provide the chloro-substituted benzylhydroxamic acid <strong>14b</strong> resulted in a ten-fold improvement of the IRAP inhibition with an IC₅₀ value of 60 nM. The binding modes of <strong>1b</strong> and <strong>14b</strong> were determined by free energy perturbation (FEP) analysis performed on candidate docking poses, determining a binding mode that accurately explained the experimental SAR. Further FEP studies of compound <strong>14b</strong> suggested that it exhibits selectivity towards IRAP over Aminopeptidase N (APN), indicating its potential for targeted therapeutic applications.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100215"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}