European Journal of Medicinal Chemistry Reports最新文献

{"title":"Investigation in the CB1 and CB2 receptor binding profile and intrinsic activity of (−) and (+)-enantiomers of some naturally occurring phytocannabinoids or synthetic derivatives","authors":"Santiago Rodríguez-Carreiro ,&nbsp;María Gómez-Cañas ,&nbsp;Francesca Lubrini ,&nbsp;Claudia Gonzalo-Consuegra ,&nbsp;Matthias Winkler ,&nbsp;Diego Caprioglio ,&nbsp;Giovanni Appendino ,&nbsp;Concepción García ,&nbsp;Paula Morales ,&nbsp;Nadine Jagerovic ,&nbsp;Joerg T. Fischer ,&nbsp;Bernd L. Fiebich ,&nbsp;Marcus R. Goetz ,&nbsp;Eduardo Muñoz ,&nbsp;Javier Fernández-Ruiz","doi":"10.1016/j.ejmcr.2025.100262","DOIUrl":"10.1016/j.ejmcr.2025.100262","url":null,"abstract":"<div><div>Cannabidiol (CBD) and cannabidivarin (CBDV) have shown promising clinical efficacy for the management of epilepsy, and beneficial effects have been demonstrated for CBD in a diversity of other pathologies (pain, schizophrenia, Tourette syndrome, anxiety). However, the mechanism(s) involved are still largely elusive, as are the molecular target(s) involved. CBD and CBDV do not orthosterically bind the cannabinoid type-1 (CB₁) and type-2 (CB₂) receptors, showing only modest allosteric modulation of both end-points. CBD and CBDV are biosynthesized as optically highly pure (−)-enantiomers, and most bioactivity data refer to these forms. (+)-CBD and related analogues [(+)-cannabidiolic acid (CBDA), its esters, and (+)-CBDV] can be obtained by chemical synthesis, and we present evidence that the (+)- and (−)-enantiomers of CBD, CBDV and of a selection of derivatives of CBDA have distinct binding profiles and functional activity at the CB₁/CB₂ receptors. Thus, with the single exception of the methyl ester of CBDA, all the (+)-enantiomers showed higher affinities than the (−)-isomers for both receptors, in particular for the CB₂ receptors. The affinity of the (+)-enantiomers for both CB₁ and CB₂ receptors showed a marked dependence on the nature of the alkyl residue on the aromatic ring and the esterification pattern of CBDA. Potency was rarely in the low nM value for CB₁, but generally so for CB₂. Enantiomers showing low nM activity were further investigated for their intrinsic activity using GTPγS binding assays. This proved that (+)-CBD, (+)-CBDV and the methyl ester of (+)-CBDA are agonists at the CB₂ receptor, with the β-hydroxyethyl ester of (+)-CBDA being an inverse agonist, and its β-hydroxypentyl ester behaving as an agonist at CB₁ and an inverse agonist at CB₂. Finally, we assayed <em>in vitro</em> the anti-inflammatory and neuroprotective properties of three compounds [(+)-CBD, (+)-CBDV and (+)-CBDA methyl ester] strongly activating CB₂, showing their ability to reduce the production of proinflammatory factors and protecting neurons against their toxicity. Remarkably, these benefits were eliminated by the selective blockade of the CB₂ receptor, highlighting its role as a (+)-CBD target. In summary, our data show that remarkable differences between (−)- and (+)-enantiomers of CBD, CBDV and related compounds exist in terms of CB₁/CB₂ receptor binding profile and intrinsic activity. The observation that the natural (−)-enantiomers do not bind CB₂ receptors suggests that their effects are associated with different targets.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100262"},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816360","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":"Benzo[b]thiophene-based 5-lipoxygenase inhibitors: A comprehensive review of therapeutic advances","authors":"Muhammed Jamshad Kongath ,&nbsp;Ameena Salim","doi":"10.1016/j.ejmcr.2025.100261","DOIUrl":"10.1016/j.ejmcr.2025.100261","url":null,"abstract":"<div><div>Heterocyclic compounds have an irreplaceable position in medicinal chemistry. Almost all bioactive natural products have heteroatoms in their active components. Benzo[b]thiophene is one of the important compounds among them. Several drugs contain benzo[b]thiophene as a potential portion responsible for pharmacological action. Zileuton, a potential 5-LOX inhibitor, is such a compound, having a benzo[b]thiophene ring as a crucial structural feature. Some of the previous research works revealed that a major side effect of zileuton is hepatotoxicity, which is found to be due to the presence of N-hydroxyurea attached to the benzo[b]thiophene ring. In this review article, we performed a systematic review of previous works for structural modification on the benzo[b]thiophene ring to improve its biological activity against the 5-LOX enzyme. Also, we compared the structure and biological activity and conducted a brief study of the structural activity relationship of the benzo[b]thiophene ring against the 5-LOX enzyme. Finally, we concluded that some positions of the benzo[b]thiophene ring are literally prone to an increase in 5-LOX inhibition after substituting with privileged motifs. So, substitution on the benzo[b]thiophene ring is able to develop much better 5-LOX inhibitors in the future.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100261"},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696907","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":"Lauric acid conjugated ureido derivatives of 2-(4-aminopiperidin-4-yl)acetic acid (β3,3-Pip): Overcoming resistance and outperforming standard antibacterials","authors":"Mohamad Mosa Mubarak ,&nbsp;Rubina Chowdhary ,&nbsp;Junaid ur Rahim ,&nbsp;Hadiya Amin Kantroo ,&nbsp;Zubair Ahmad Wani ,&nbsp;Abbass Malik ,&nbsp;Shuhaab Shah ,&nbsp;Ishfaq Ahmad Baba ,&nbsp;Aminur R. Sarkar ,&nbsp;Rajkishor Rai ,&nbsp;Zahoor Ahmad","doi":"10.1016/j.ejmcr.2025.100260","DOIUrl":"10.1016/j.ejmcr.2025.100260","url":null,"abstract":"<div><div>The imperative for the expeditious development of novel antibiotics stems from the escalating resistance trends witnessed against conventional antibiotic agents. The present study delineates the synthesis, characterization, and antibacterial efficacy of β,β-disubstituted-β-amino acid derivatives, specifically those capped with lauric acid at the N-terminus through amide and urea bonds, LA-β^3,3-Pip-PEA, <strong>1</strong>; LA-β^3,3-Pip(G)-PEA, <strong>2</strong>; LA^U-β^3,3-Pip-PEA, <strong>3</strong>; and LA^U-β^3,3-Pip(G)-PEA, <strong>4</strong>. Against <em>E. coli</em>, <em>S. aureus,</em> and <em>E. faecalis</em> LA^U-β^3,3-Pip-PEA, <strong>3</strong> exhibited robust antibacterial activity having a low minimum inhibitory concentration (MIC) of 0.5 μg/mL. It also showed a remarkable MIC of 8 μg/mL and 16 μg/mL against MRSA and MDR <em>E. coli</em> respectively outperforming amoxicillin, cefpodoxime, and 10 other standard antibiotics. It also synergized with antibiotics like Ciprofloxacin, Streptomycin, and Ampicillin. Mechanistic insights revealed membrane disruption in <em>E. coli</em> and <em>S. aureus</em> upon treatment with compound <strong>3</strong>. Compound <strong>3</strong> maintained complete cell viability across observed cell lines; AML12, RAW 264.7, and HEK-293 at concentrations of 1 μg/mL and 10 μg/mL. Demonstrating notable stability, compound <strong>3</strong> resisted trypsin degradation and maintained antibacterial efficacy across diverse temperatures and pH conditions. Concentration-dependent reductions in swimming and swarming movements associated with <em>E. coli</em> flagella showed compound <strong>3</strong>'s potential against biofilm development at both MIC and sub-MIC concentrations. Notably, after minimal exposure, compound <strong>3</strong> exhibited a 4-h Post-Antibiotic Effect (PAE) i.e. halting bacterial growth. Compound <strong>3</strong> also demonstrated DNA binding at 64 μg/mL, retarding bacterial DNA movement in agarose gel electrophoresis. In a mouse wound infection model, compound <strong>3</strong> outperformed mupirocin, sterilizing 7 logs CFU of <em>S. aureus</em> in just 2 days, achieving full wound closure by Day 6, and early cessation of pus, showcasing its superior therapeutic efficacy.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100260"},"PeriodicalIF":0.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687362","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":"Design, synthesis, and biological evaluation of new tetrahydropyrimidine derivatives as multitarget anti-inflammatory agents","authors":"Ahmed R. Ali ,&nbsp;Ahmed K. Al-Kubeisi ,&nbsp;Bassma H. Elwakil ,&nbsp;Amira Abd-Elfattah Darwish ,&nbsp;Tahani M. Almutairi ,&nbsp;Maram M. Elshatanofy ,&nbsp;Tareq Q. Alshargabi ,&nbsp;Maged A. El Sawy","doi":"10.1016/j.ejmcr.2025.100259","DOIUrl":"10.1016/j.ejmcr.2025.100259","url":null,"abstract":"<div><div>In an innovative strategy for addressing inflammatory conditions, new 2-oxo-1,2,3,4-tetrahydropyrimidine derivatives were synthesized and subsequently assessed for their multitarget anti-inflammatory effects on various biomarkers, including IL-6, TNF-α, IL-1β, NF-κB, iNOS, MAPK, and ERK, through <em>in vitro</em> experimentation. The presence of LPS was found to significantly increase the levels of IL-6, TNF-α, and IL-1 beta. However, treatment with the tetrahydropyrimidine derivatives, especially compound <strong>4d</strong> with an IC₅₀ value of 0.4–0.69 μM, led to a substantial reduction in these cytokine levels. Furthermore, LPS was observed to upregulate the expression of MAPK and ERK, as well as NF-κB and iNOS, but these were significantly diminished following treatment with the tetrahydropyrimidines, particularly the compound identified as <strong>4d</strong>, which exhibited an IC₅₀ value of 0.2–0.62 μM for NF-κB, iNOS and MAPK. The molecular docking studies conducted on the three enzymes revealed notable binding characteristics and affinities, thereby reinforcing their biological functions.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100259"},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548638","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":"Design, synthesis, and biological evaluation of substituted benzyl-triazolopyridine derivatives as non-hydroxamate based HDAC8 inhibitors","authors":"N.V.M. Rao Bandaru ,&nbsp;Ashna Fathima ,&nbsp;Vandana Joshi ,&nbsp;Markus Schweipert ,&nbsp;Obanna Pathur ,&nbsp;Kosana Sai Chaitanya ,&nbsp;Trinath Jamma ,&nbsp;Vivek Sharma ,&nbsp;Chandrasekhar Abbineni ,&nbsp;Franz-Josef Meyer-Almes ,&nbsp;Kondapalli Venkata Gowri Chandra Sekhar","doi":"10.1016/j.ejmcr.2025.100255","DOIUrl":"10.1016/j.ejmcr.2025.100255","url":null,"abstract":"<div><div>Traditional Histone deacetylase 8 (HDAC8) inhibitors primarily rely on hydroxamate-based scaffolds. However, there is a growing interest in developing non-hydroxamate inhibitors to overcome potential limitations with hydroxamate-based inhibitors. In this study, we report the design, synthesis, and evaluation of a series of benzyl-1,2,4-triazolo [4,3-a] pyridine derivatives as non-hydroxamate HDAC8 inhibitors. Their HDAC8 inhibitory activities were assessed by enzymatic assay. Active compounds from the HDAC8 enzymatic assay were evaluated in various cancer cell lines, revealing that compound <strong>9i</strong> demonstrated significant anti-neuroblastoma activity. Docking studies on compound <strong>9i</strong> were conducted to explicate its structural basis. The additional experiments showed that compound <strong>9i</strong> inhibited colony formation, induced hyperacetylation of SMC3, suppressed cell migration, triggered apoptosis, and caused cell cycle arrest in IMR-32 neuroblastoma cells. Overall, these inhibitors showed promising activity and a strong correlation with observed phenotypic effects, suggesting their potential for further development as therapeutic agents for cancer treatment.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100255"},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143548631","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":"Structural optimization of indolizinoindolones to obtain potent new antimalarials with dual stage activity","authors":"Paulo A.F. Pacheco ,&nbsp;Ricardo J.F. Ferreira ,&nbsp;Diana Fontinha ,&nbsp;Caroline Conceição Sousa ,&nbsp;Jenny Legac ,&nbsp;Valentina Barcherini ,&nbsp;Philip J. Rosenthal ,&nbsp;Miguel Prudêncio ,&nbsp;Diogo R.M. Moreira ,&nbsp;Maria M.M. Santos","doi":"10.1016/j.ejmcr.2025.100258","DOIUrl":"10.1016/j.ejmcr.2025.100258","url":null,"abstract":"<div><div>Malaria continues to represent a major public health concern due to the emergence of resistance to most available drugs. We report the optimization of the indolizinoindolone scaffold to increase activity against erythrocytic stages of <em>Plasmodium</em> (<em>P.</em>) <em>falciparum</em> and against hepatic stages of the rodent parasite <em>P. berghei</em>. Twenty-six enantiopure indolizinoindolones were synthesized, with IC₅₀ values in the low micromolar and sub-micromolar range against both stages, and no significant cytotoxicity against mammalian cell lines. The most active compound showed nanomolar activity against <em>P. falciparum</em> blood stages <em>in vitro</em>, low micromolar activity against hepatic <em>P. berghei</em> infection <em>in vitro</em>, and a 7-fold higher selectivity index than that of chloroquine. This compound was also tested in <em>P. berghei</em>-infected mice, inhibiting the development of parasitemia relative to untreated mice. Overall, we identified a new set of lead antimalarial compounds. Further optimization of the pharmacokinetic properties of this scaffold is warranted.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100258"},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579734","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":"Corrigendum to: Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review [Eur. J. Med. Chem. Rep. 5]","authors":"Muhammad Salman Hameed ,&nbsp;Hongxuan Cao ,&nbsp;Li Guo ,&nbsp;Lei Zeng ,&nbsp;Yanliang Ren","doi":"10.1016/j.ejmcr.2025.100254","DOIUrl":"10.1016/j.ejmcr.2025.100254","url":null,"abstract":"","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100254"},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600502","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":"Dicentrine and its N-oxide derivatives induces apoptotic and necrotic cell death in prostate cancer cell lines","authors":"Ranyelison S. Machado ,&nbsp;Daniela C. Tristão ,&nbsp;Natália M. Araújo ,&nbsp;Elias Jorge Muniz Seif ,&nbsp;Kayo Alexandre S. da Cruz ,&nbsp;Mirian G. Morale ,&nbsp;Ileana Gabriela S. de Rubio ,&nbsp;João Henrique G. Lago ,&nbsp;Rodrigo E. Tamura","doi":"10.1016/j.ejmcr.2025.100257","DOIUrl":"10.1016/j.ejmcr.2025.100257","url":null,"abstract":"<div><div>As part of our continuous research for the discovery of anticancer natural products, the effects of alkaloid (6a<em>S</em>)-dicentrine (<strong>1</strong>) and its respective (6a<em>S</em>,6<em>S</em>)- (<strong>1a</strong>) and (6a<em>S</em>,6<em>R</em>)-(<strong>1b</strong>) <em>N</em>-oxides against two prostate cancer cell lines (PC3 and DU145) were evaluated for the first time. Alkaloid <strong>1</strong> exhibited IC₅₀ values of 18.43 and 23.53 μM for both tested cells. On the other hand, <strong>1a</strong> demonstrated higher IC₅₀ values (46.36 and 33.85 μM) whereas <strong>1b</strong> displayed reduced activity (IC₅₀ &gt; 50 μM) for both cells. These results suggest that the stereochemistry of the <em>N</em>-oxide moiety plays an important role in the antitumor activity. Molecular docking indicated differential residue interactions between compounds <strong>1</strong>, <strong>1a</strong>, and <strong>1b</strong> with EGFR and TP53 which could result in their differential modulation. Alkaloid <strong>1</strong> induced strong necrotic and apoptotic cell death in all tested cell lines, while <strong>1a</strong> caused reduced necrotic and apoptotic cell death in PC3, a TP53-null cell line, moderate necrotic cell death in DU145, a mutant TP53 cell line, and strong necrotic death in HEK293, an embryonic kidney cell line with wild-type TP53. Alkaloid <strong>1b</strong> did not induce the death of PC3, but induced necrotic cell death in both DU145 and HEK293. The alkaloids were shown to efficiently modulate gene and protein expression and activate TP53 and EGFR pathways with potential implications for targeting tumors with specific TP53 mutations. Altogether, the obtained results showed that (6a<em>S</em>)-dicentrine (<strong>1</strong>) and its N-oxide derivatives, especially <strong>1a</strong>, displayed potential as antitumor agents and justify its continued investigation as a therapeutic candidate.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100257"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528732","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":"Potential of apitherapy in the management of cardiovascular diseases","authors":"Rimpa Karmakar,&nbsp;Sakshi Soni,&nbsp;Vandana Soni,&nbsp;Umesh Kumar Patil","doi":"10.1016/j.ejmcr.2025.100256","DOIUrl":"10.1016/j.ejmcr.2025.100256","url":null,"abstract":"<div><div>Apitherapy has been used as an adjunctive medical practice in several countries, and bee products or apitherapeutic agents are being consistently utilized for millennia by humanity to treat and prevent an assortment of illnesses. This review sought to explore the relationship between apitherapy and scientific research and experimental trials utilizing bee products within the domain of cardiology. Numerous studies conducted <em>in vivo</em> along with <em>in vitro</em> indicate that these products may have potential benefits in the prevention and management of cardiovascular diseases (CVDs). This concise review of research reveals new facets of the biological activities of many bee products: honey, propolis, bee venom, pollen, royal jelly, beeswax, and bee bread, as naturally occurring and intriguing remedies for common CVDs. There are undoubtedly some intriguing mechanisms in bee products that aid in the treatment and prevention of CVDs. Future research with larger sample sizes and improved techniques is needed to validate the relationship between bee products and CVD risk factors. Conclusively, bee products seem to have the potential to lower cardiovascular disease risk factors; however, more research is required to fully grasp these benefits. Even if our knowledge of bee products has greatly expanded, it is still crucial to fully utilize its potential, standardize its use, and share the results in academic and non-academic settings to further investigate its potential in the area of cardiology.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100256"},"PeriodicalIF":0.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487774","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":"New heterocyclic A1/A3 adenosine receptor ligands through molecular simplification strategies","authors":"Letizia Crocetti ,&nbsp;Abigail Pearce ,&nbsp;Venkat S. Vege ,&nbsp;Qi Xu ,&nbsp;Jing Xu ,&nbsp;Hannes Buthmann ,&nbsp;Maria Paola Giovannoni ,&nbsp;Gabriella Guerrini ,&nbsp;Francesca Catarzi ,&nbsp;Silvia Selleri ,&nbsp;Xianglin Huang ,&nbsp;Aneesh Chandran ,&nbsp;Graham Ladds ,&nbsp;Agostino Cilibrizzi","doi":"10.1016/j.ejmcr.2025.100253","DOIUrl":"10.1016/j.ejmcr.2025.100253","url":null,"abstract":"<div><div>In this paper we report the synthesis of new A₁/A₃ adenosine receptor antagonists designed as simplification products of the A₁ antagonists with pyrazolo[1′,5′:1,6]pyrimido [4,5-d]pyridazin-4(3H)-one scaffold previously developed by us. Notably, selective A₁R antagonists are promising therapeutic agents in Alzheimer's disease and for the treatment of cognitive deficits, while A₃R antagonists are potentially useful in the treatment of ischemia and certain types of cancer. Initial screening with NanoBRET competition binding assay revealed a number of products with pKi ≥5 for A₁R and A₃R. For some representative compounds the antagonist profiles, as well as their selectivity versus A_2AR and A_2BR, have been also validated by antagonizing NECA in cAMP accumulation. The most interesting compounds resulted the A₁/A₃ mixed antagonist <strong>3b</strong> (pKi = 6.41 and 6.29 for A₁R and A₃R respectively, pKb = 5.00 and 5.27 for the A_2aR and A_2bR) and the selective A₃R antagonist <strong>5c</strong> (pKi = 6.40, pKb values of 4.44, 6.17, 4.16, and 4.78 for the A₁R, A₃R, A_2aR and A_2bR, respectively). Furthermore, <em>in silico</em> simulations were carried out to study the molecular mechanism of the high affinity of <strong>3b</strong> for A₁/A₃Rs as well as the selectivity of <strong>5c</strong> for A₃R over A₁R. Overall, this work highlights new series of bicyclic small-molecules as valid candidates for further structural optimization towards the development of therapeutically relevant A₁/A₃ adenosine receptor antagonists.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100253"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454594","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}