MedChemComm最新文献

{"title":"2-Oxoindolin-thiazoline hybrids as scaffold-based therapeutics for T2DM-associated cognitive impairment: design, synthesis, in vitro and in silico studies","authors":"Wesam S. Qayed, Mostafa A. Hassan, Halil Şenol, Parham Taslimi and Tarek Aboul-Fadl","doi":"10.1039/D5MD00628G","DOIUrl":"10.1039/D5MD00628G","url":null,"abstract":"<p >Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are closely linked neurodegenerative and metabolic disorders, sharing overlapping pathological mechanisms. In this study, structure-based drug design combined with molecular hybridization strategies was employed to develop dual-acting compounds targeting both conditions. A series of twenty hybrid molecules, comprising 2-oxoindolin-3-thiosemicarbazones (<strong>3a–i</strong>) and thiazolines (<strong>4a–k</strong>) were successfully synthesized and characterized using spectroscopic techniques and elemental analysis. Biological evaluations demonstrated that compounds <strong>3d</strong> and <strong>3h</strong> exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose. These findings highlight their promising antidiabetic potential and support further investigation into their therapeutic relevance for AD and T2DM comorbidity (<strong>3d</strong> (α-glucosidase <em>K</em><small>_i</small> = 41.41 ± 2.53 nM; α-amylase IC<small>₅₀</small> = 1.25 ± 0.02 nM), <strong>3h</strong> (α-glucosidase <em>K</em><small>_i</small> = 44.19 ± 2.41 nM; α-amylase IC<small>₅₀</small> = 2.87 ± 0.16 nM and <strong>acrabose</strong> (α-glucosidase <em>K</em><small>_i</small> = 101.20 ± 7.53, α-amylase IC<small>₅₀</small> 9.73 ± 0.20). Furthermore, compounds <strong>3i</strong> and <strong>4i</strong> exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine. Notably, compound <strong>4i</strong> demonstrated exceptional multi-enzyme inhibition, with kinetic parameters indicating strong binding affinity: <strong>3i</strong> (AChE <em>K</em><small>_i</small> = 59.71 ± 2.24 nM; BChE <em>K</em><small>_i</small> = 8.43 ± 0.97 nM), <strong>4i</strong> (AChE <em>K</em><small>_i</small> = 53.31 ± 1.74 nM; BChE <em>K</em><small>_i</small> = 10.72 ± 2.19 nM), and <strong>tacrine</strong> (AChE <em>K</em><small>_i</small> = 132.35 ± 5.90 nM; BChE <em>K</em><small>_i</small> = 137.42 ± 4.01 nM). Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, <em>in silico</em> ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 317-342"},"PeriodicalIF":3.597,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning prediction of acute toxicity with in vivo experiments on tetrazole derivatives","authors":"Danil P. Zarezin, Alexander A. Shtil, Valentin G. Nenajdenko and Sophia S. Borisevich","doi":"10.1039/D5MD00757G","DOIUrl":"10.1039/D5MD00757G","url":null,"abstract":"<p >This study investigates the application of machine learning techniques to predict the toxicity of tetrazole derivatives, aiding in the identification of environmental risks from chemical exposure. Utilizing LD<small>₅₀</small> data sourced from the scientific literature and the ChemIDplus database, regression models were developed to forecast acute intraperitoneal toxicity in mice. A machine learning regression model for acute intraperitoneal toxicity in mice was constructed and validated on a test dataset, achieving high accuracy (<em>R</em><small>²</small> = 0.76 and MSE below 10<small>⁻⁴</small>) and surpassing most of the comparable literature models. Molecular descriptors were computed <em>via</em> Mordred software to explore quantitative structure–activity relationships, and additionally, the model's robustness was demonstrated by measuring the acute toxicity of tetrazole derivatives synthesized through the azido-Ugi reaction.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 494-505"},"PeriodicalIF":3.597,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145638399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure–activity relationships of hydrophobic small molecule irreversible inhibitors of tissue transglutaminase","authors":"Daniel A. Wallace, Sarah Tribe, Pauline Navals, Christina Bi, Tarasha Sharma and Jeffrey W. Keillor","doi":"10.1039/D5MD00815H","DOIUrl":"10.1039/D5MD00815H","url":null,"abstract":"<p >Tissue transglutaminase (TG2) is both an enzyme and a G-protein that is implicated in many diseases, such that small molecule inhibitors of TG2 have broad potential as drugs or research tools. Previous work has demonstrated how the structure of EB-2-16, a highly potent irreversible inhibitor of TG2, has been optimised with respect to its warhead, tether and bridge moieties. In this work, we studied the structure–activity relationships of the pendant hydrophobic group of the scaffold. This confirmed the superior affinity conferred by the parent adamantyl moiety, over other cycloalkyl, aryl, biaryl and bridged biaryl groups. Additionally, some substituted adamantyl derivatives were shown to exhibit superior inhibitory efficiency over the parent inhibitor, with <em>k</em><small>_inact</small>/<em>K</em><small>_I</small> values over 10<small>⁶</small> M<small>⁻¹</small> min<small>⁻¹</small>. The best inhibitors were shown to exhibit excellent lipid membrane permeability, but evaluation of their human hepatocyte stability revealed a sharp distinction between them. Despite the bromo- and iodoadamantyl derivatives being more efficient inhibitors, chloroadamantyl inhibitor <strong>25b</strong> exhibits the best overall properties (<em>k</em><small>_inact</small> = 1.69 min<small>⁻¹</small>, <em>K</em><small>_I</small> = 1.79 μM, <em>k</em><small>_inact</small>/<em>K</em><small>_I</small> = 941 × 10<small>³</small> M<small>⁻¹</small> min<small>⁻¹</small>, <em>P</em><small>_e</small> = 1.41 × 10<small>⁻⁶</small> cm s<small>⁻¹</small>, CL<small>_int</small> = 6.91 μL min<small>⁻¹</small>/10<small>⁶</small> cells) and suitability for potential applications <em>in vivo</em>.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 422-451"},"PeriodicalIF":3.597,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12631574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588713","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":"Exploring pyrazolidinone and pyrazolidinedione scaffolds for Alzheimer's therapy: multitarget COX-2 inhibitors with anti-amyloid β, anti-tau, antioxidant, and neuroprotective activities","authors":"Michael Emad, Reham Waheed, Zeinab Mostafa, Sarah S. Darwish, Rosa Purgatorio, Daniela Valeria Miniero, Annalisa De Palma, Tzu-Peng Cheng, Yu-Cheng Chen, Moustafa Gabr, Ahmed M. El Kerdawy, Marco Catto, Ashraf H. Abadi, Tsong-Long Hwang and Mohammad Abdel-Halim","doi":"10.1039/D5MD00802F","DOIUrl":"10.1039/D5MD00802F","url":null,"abstract":"<p >COX-2 enzyme is implicated in Alzheimer's disease (AD) through amyloid beta (Aβ) accumulation, tau aggregation, and neuroinflammation. However, clinical outcomes of COX-2 inhibitors in AD have been inconsistent. This study explores a novel series of pyrazolidinones and pyrazolidinediones as selective COX-2 inhibitors. Among these, 4-hydrazonopyrazolidinediones exhibited potent COX-2 inhibition, reducing PGE2 release in a THP-1 cell model. Compounds <strong>15</strong> and <strong>16</strong> demonstrated multitargeting potential by inhibiting Aβ and tau aggregation (PHF6 and R3) and showed significant neuroprotective effects against Aβ and H<small>₂</small>O<small>₂</small>-induced toxicity in SH-SY5Y cells without cytotoxicity. Additionally, both compounds displayed high permeability in PAMPA and MDCK-MDR1 assays, indicating their potential to cross the blood–brain barrier and reach therapeutic targets. These findings highlight the potential of reviving COX-2 inhibitors as multitargeted therapeutic agents for AD, offering a promising strategy to address multiple pathological aspects of the disease, including neuroinflammation, amyloid aggregation, and tau pathology.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 630-657"},"PeriodicalIF":3.597,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of isoxazole-functionalized benzene sulphonamides as novel inhibitors of Mycobacterium tuberculosis β-carbonic anhydrases","authors":"Rani Bandela, Anuradha Singampalli, Sarvan Maddipatla, Pardeep Kumar, Sri Mounika Bellapukonda, Rajendhar Ramavath, Lina S. Mahajan, Srinivas Nanduri, Divya Vemula, Aman Dalal, Nitin Pal kalia, Vasundhra Bhandari, Paola Gratteri, Niccolò Paoletti, Alessandro Bonardi, Claudiu T. Supuran and Venkata Madhavi Yaddanapudi","doi":"10.1039/D5MD00744E","DOIUrl":"10.1039/D5MD00744E","url":null,"abstract":"<p >The escalating prevalence of multidrug-resistant tuberculosis (MDR-TB) underscores the urgent need for new classes of antitubercular agents targeting novel pathways. Carbonic anhydrase, a ubiquitous metalloenzyme, catalyses the reversible hydration of carbon dioxide in the CO<small>₂</small> + H<small>₂</small>O <img> HCO<small>₃</small><small>⁻</small> + H<small>⁺</small> reaction. Suppressing this enzymatic activity has recently been identified as a new pathway for the treatment of <em>Mycobacterium tuberculosis</em>. To address this, a series of isoxazole–sulphonamides was rationally designed, incorporating an isoxazole pharmacophore as the aromatic tail, amide as a linker, and sulphonamide as the zinc-binding group. These compounds were evaluated against <em>Mycobacterium tuberculosis</em> carbonic anhydrases (MtCA 1 and 3) and two human carbonic anhydrases (hCA I and II) to identify selective inhibitors of the bacterial enzymes. The findings indicated that molecules containing an isoxazole pharmacophore with amide-linked benzene-3-sulphonamide were significantly more selective for MtCA 3 than hCA I and II. Among these compounds, <strong>12c</strong>, <strong>12e</strong>, and <strong>19b</strong> had the highest inhibition against the MtCA 3 with <em>K</em><small>_i</small> values between 0.08–0.09 μM compared to the standard acetazolamide with a <em>K</em><small>_i</small> value of 0.10 μM. Some of the best compounds exhibited potent and selective inhibition of MtCA 3 over hCA I and II, with the <em>meta</em>- and <em>para</em>-substituted derivatives demonstrating higher selectivity and stronger inhibition. Specifically, compound <strong>19b</strong> proved to be 199 and 38 times more selective for MtCA 3 than hCA I and hCA II respectively, compared to the standard drug acetazolamide, which is a non-selective CA inhibitor. The potential of compound <strong>19b</strong> as a promising antitubercular agent with a MIC value of 8 μg mL<small>⁻¹</small> against mc<small>²</small> 6230 was further strengthened by <em>in silico</em> ligand–target interaction studies. Thus, compound <strong>19b</strong> is emphasised as a promising lead in the pursuit of new, selective agents targeting MtCA 3.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 6368-6379"},"PeriodicalIF":3.597,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel chalcone 2-thiopyrimidine conjugates as dual VEGFR-2/BRAF inhibitors: design, synthesis, in vitro cytotoxicity, and molecular docking study","authors":"Randa Atef Ibrahim Abdelaziz, Heba Abdelrasheed Allam, Ahmed Mahmoud El Kerdawy, Mahmoud Taha Abo-Elfadl, Safinaz El-Sayed Abbas and Iman Ahmed Youssef Ghannam","doi":"10.1039/D5MD00787A","DOIUrl":"10.1039/D5MD00787A","url":null,"abstract":"<p >Chalcone-based derivatives have shown potential anticancer activity <em>via</em> multiple mechanisms including protein kinase inhibition. In the current study, two series of chalcone/2-thiopyrimidine conjugates <strong>4a–4d</strong> and <strong>6a–6i</strong> were designed, synthesized and screened for their antiproliferative activity in a single-dose assay against NCI-60 cancer cell lines. Ten compounds, <strong>4a–4d</strong>, <strong>6a–6c</strong>, <strong>6f</strong>, <strong>6h</strong>, and <strong>6i</strong>, were selected for a five-dose assay and their GI<small>₅₀</small> values were determined. Compound <strong>4c</strong> showed potent anticancer activity against LOX IMVI melanoma cell line with a GI<small>₅₀</small> value of 0.0128 μM. Seven compounds, <strong>4a</strong>, <strong>4c</strong>, <strong>4d</strong>, <strong>6c</strong>, <strong>6f</strong>, <strong>6h</strong>, and <strong>6i</strong>, were found to be non-cytotoxic against fibroblast (hFB) normal cell line. Additionally, investigation of the VEGFR-2 inhibitory activity of the ten promising compounds revealed that <strong>4c</strong>, <strong>4d</strong> and <strong>6i</strong> displayed promising VEGFR-2 inhibition (IC<small>₅₀</small> = 0.144, 0.105, and 0.072 μM, respectively) compared to sorafenib (IC<small>₅₀</small> = 0.081 μM). Moreover, <strong>4c</strong> inhibited BRAF<small>_WT</small> and BRAF<small>_V600E</small> kinases (IC<small>₅₀</small> = 0.201 and 0.101 μM, respectively) relative to vemurafenib (IC<small>₅₀</small> = 0.156 and 0.063 μM, respectively). Furthermore, <strong>4c</strong> arrested the cell cycle progression at the G<small>₁</small> phase and induced late apoptosis in LOX IMVI cells. Moreover, evaluation of the effect of <strong>4c</strong> on apoptotic markers in the mentioned cells indicated an increase in the Bax/Bcl-2 ratio by 28.12-fold along with upregulation of caspases-3 and -9 by 7.40- and 5.63-fold, respectively, in addition to anti-migratory effect. Molecular docking study of the most promising derivatives revealed a common binding pattern in the binding site of the target kinases that extends from the hinge region through the gate area towards the allosteric back pocket interacting with the key amino acids in a type II inhibitor-like binding pattern.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 6299-6318"},"PeriodicalIF":3.597,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of lupeol-derived triterpenic azines as potential neuroprotective agents","authors":"Florencia A. Musso, Natalia P. Alza, Gabriela A. Salvador and María Belén Faraoni","doi":"10.1039/D5MD00753D","DOIUrl":"10.1039/D5MD00753D","url":null,"abstract":"<p >Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the accumulation of α-synuclein aggregates. Current treatments are primarily symptomatic, highlighting the need for new neuroprotective strategies. Natural triterpenes have shown promise in neurodegenerative diseases, and structural modifications can enhance their bioactivity. In this study, we obtained a series of new triterpenic azines (<strong>4a–4p</strong>) from lupeol, optimizing reaction conditions through microwave-assisted synthesis. The neuroprotective potential of these derivatives was evaluated in human neuroblastoma IMR-32 cells exposed to 6-hydroxydopamine (6-OHDA), a widely used <em>in vitro</em> model of PD. Compounds <strong>4c</strong>, <strong>4m</strong>, and <strong>4n</strong> significantly prevented 6-OHDA-induced cytotoxicity, restoring cell viability at 10 and 50 μM to control levels. Since ferroptosis is a cell death mechanism implicated in PD, we further examined the effects of these compounds in N27 dopaminergic neurons exposed to the ferroptosis inducers RSL3 and erastin. Among the tested derivatives, <strong>4c</strong> exhibited a remarkable protective effect against RSL3-induced ferroptosis, which was comparable to ferrostatin-1, displaying an IC<small>₅₀</small> value of 9.1 μM. These findings support the development of triterpenic azines as neuroprotective agents and warrant further investigation in preclinical PD models.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 618-629"},"PeriodicalIF":3.597,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure–activity relationship of GSK-3β inhibitors: insight into drug design for Alzheimer's disease","authors":"G. Rajamani, Saba Naqvi and Abha Sharma","doi":"10.1039/D5MD00211G","DOIUrl":"10.1039/D5MD00211G","url":null,"abstract":"<p >Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive impairment, memory loss, and decline in thinking and learning skills. The exact pathophysiology of the disease is still unknown; however, theories such as tau hyperphosphorylation, amyloid-β (Aβ) aggregation, and cholinergic dysfunction explain its pathogenesis. A few available drugs provide only symptomatic relief, while recently approved monoclonal antibody-based drugs target aggregated amyloid beta clearance. Extensive research is ongoing for drug development targeting various pathways, where one of the targets is glycogen synthase kinase (GSK-3β). GSK-3β plays diverse roles in physiological functions, and its dysregulation may lead to pathological conditions such as Alzheimer's disease (AD). GSK-3β comprises serine and threonine residues, is responsible for phosphorylation of the tau protein, and activates the amyloid precursor protein (APP) to synthesise Aβ. Consequently, the abnormal functioning of GSK-3β leads to hyperphosphorylation of the tau protein, and the formation of Aβ plaques eventually leads to neurofibrillary tangles. To develop GSK-3β inhibitors, one must know the requirements of crucial structural features in drug candidates to act at the active site for interaction. This review focuses on the latest pool of GSK-3β inhibitors and their design strategy, structure–activity relationship (SAR), molecular docking, and permeability across the brain layers. This broad review collection may benefit readers by providing the structural requirements to develop new GSK-3β inhibitors for treating AD.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 15-51"},"PeriodicalIF":3.597,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the antimicrobial potential of boron cluster compounds","authors":"William J. Price Cunliffe, Peter J. Rutledge and Louis M. Rendina","doi":"10.1039/D5MD00862J","DOIUrl":"10.1039/D5MD00862J","url":null,"abstract":"<p >Since their discovery in the mid-20th century, inorganic boron clusters such as carboranes, metallacarboranes, and dodecaborates have been investigated for a range of medicinal applications, most notably as boron delivery agents for boron neutron capture therapy. Increasingly, boron cluster-containing compounds have also been studied for their antimicrobial activity as scientists seek new ways to address the growing global threat of antimicrobial resistance. Boron cluster compounds have a number of properties that make them promising antimicrobial agents, including high lipophilicity and stability, low toxicity, resistance to enzymatic metabolism, unusual ‘dihydrogen’ bonding, as well as the ability to cross or disrupt cell membranes, or carry other molecules through them. In this review, we summarise and critically evaluate the antibacterial, antifungal, antiviral, and antimalarial boron cluster compounds reported to date, with a focus on the past five years of research. We highlight medicinal chemistry opportunities where boron clusters may deliver anti-infective value beyond that of traditional carbon-based scaffolds.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 65-79"},"PeriodicalIF":3.597,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of spirodioxolane nsP2 helicase inhibitors with antialphaviral activity","authors":"Hans J. Oh, John D. Sears, Bose Muthu Ramalingam, Rahman Shah Zaib Saleem, Zachary W. Davis-Gilbert, Mohammed Anwar Hossain, Stella R. Moorman, Durbadal Ohja, Sabian A. Martinez, Jane E. Burdick, Rafael M. Couñago, Nathaniel J. Moorman, Mark T. Heise, Matthew H. Todd and Timothy M. Willson","doi":"10.1039/D5MD00772K","DOIUrl":"10.1039/D5MD00772K","url":null,"abstract":"<p >We describe the design, synthesis, and antialphaviral activity of spirodioxolane inhibitors targeting the alphavirus nsP2 helicase (nsP2hel). The spirodioxolanes are a new series of direct-acting antivirals that retain key molecular features required for inhibition of nsP2hel, including a highly substituted piperidine acetamide with its associated conformational isomerism and thermal mobility. Unlike the related oxaspiropiperidine nsP2hel inhibitors, the spirodioxolanes showed no enantioselectivity in their antiviral activity. The spirodioxolanes demonstrated antialphaviral activity against the Old World alphavirus Chikungunya virus, with some analogs also showing activity against the New World alphavirus Venezuelan equine encephalitis virus. Importantly, certain spirodioxolane analogs, such as <strong>6b</strong>, maintained activity against viral mutants that displayed resistance to first-generation oxaspiropiperidine inhibitors, indicating their potential for optimization as a new class of broad-spectrum antialphaviral drugs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 1","pages":" 452-476"},"PeriodicalIF":3.597,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12643038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605644","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}