Pub Date : 2025-11-27DOI: 10.1016/j.ejmech.2025.118405
Bing Yang , Ruo-Jun Man , Qing Xie , Jie You , Jing-Yi Shi , Hong Dai , Hai-Liang Zhu
Thirty new 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated as tubulin inhibitors against cancers. Some target compounds showed relatively strong anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells. Among them, the top hit, compound C21, yielded an IC50 value of 0.08 μM against HeLa cells, exhibiting lower cytotoxicity compared to 293T cells. Tubulin polymerization inhibition assay indicated that the inhibitory activity of compound C21 (IC50: 1.59 ± 0.66 μM) was stronger than that of Colchicine (IC50: 2.52 ± 0.23 μM). Mechanism studies demonstrated that compound C21 could arrest cell cycle at the G2/M phase and induce tumor cell apoptosis in a dose- and time-dependent manner. The confocal imaging further demonstrated that compound C21 could inhibit tubulin polymerization, similar to Colchicine. Moreover, compound C21 showed excellent in vivo anti-tumor potency in a human cervical cancer xenograft mouse model with an inhibitory rate of 80.51 %, which was better than the CA-4P group (49.22 %) and the lower dose group (69.52 %). Furthermore, the docking simulation visualized the possible binding pattern of compound C21 into tubulin. Finally, the information provided in this study will be helpful for the future development of tubulin-related anti-cancer drugs.
{"title":"Design, synthesis, and biological evaluation of 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives as tubulin polymerization inhibitors with potential anti-cancer effects","authors":"Bing Yang , Ruo-Jun Man , Qing Xie , Jie You , Jing-Yi Shi , Hong Dai , Hai-Liang Zhu","doi":"10.1016/j.ejmech.2025.118405","DOIUrl":"10.1016/j.ejmech.2025.118405","url":null,"abstract":"<div><div>Thirty new 2-(benzylthio)-5-(indol-3-yl)-1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated as tubulin inhibitors against cancers. Some target compounds showed relatively strong anti-proliferative activity against HepG2, HeLa, MCF-7, and A549 cells. Among them, the top hit, compound <strong>C21</strong>, yielded an IC<sub>50</sub> value of 0.08 μM against HeLa cells, exhibiting lower cytotoxicity compared to 293T cells. Tubulin polymerization inhibition assay indicated that the inhibitory activity of compound <strong>C21</strong> (IC<sub>50</sub>: 1.59 ± 0.66 μM) was stronger than that of Colchicine (IC<sub>50</sub>: 2.52 ± 0.23 μM). Mechanism studies demonstrated that compound <strong>C21</strong> could arrest cell cycle at the G2/M phase and induce tumor cell apoptosis in a dose- and time-dependent manner. The confocal imaging further demonstrated that compound <strong>C21</strong> could inhibit tubulin polymerization, similar to Colchicine. Moreover, compound <strong>C21</strong> showed excellent <em>in vivo</em> anti-tumor potency in a human cervical cancer xenograft mouse model with an inhibitory rate of 80.51 %, which was better than the CA-4P group (49.22 %) and the lower dose group (69.52 %). Furthermore, the docking simulation visualized the possible binding pattern of compound <strong>C21</strong> into tubulin. Finally, the information provided in this study will be helpful for the future development of tubulin-related anti-cancer drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118405"},"PeriodicalIF":5.9,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.ejmech.2025.118393
Arun K. Ghosh , Rajesh Manda , Ranjith Kumar Gadi , Yueyi Chen , Natalie M. Galvan , John J.G. Tesmer
We report here design of a series of highly selective, potent, non-covalent, and drug-like G protein-coupled receptor kinase 5 (GRK5) inhibitors. GRK5 is an important target for drug development for potential treatment of heart failure and cancer. Utilizing pyrroloindolinone as the main scaffold, which is embedded in the FDA-approved, orally bioavailable anti-cancer drug, sunitinib, we used structure-based design to generate a series of noncovalent, and drug-like GRK5 inhibitors. Several compounds exhibited low nanomolar potency and high selectivity against the related kinase GRK2. Three high-resolution X-ray crystal structures of GRK5-inhibitor complexes were determined to obtain insights into the ligand-binding site interactions. The current structure-activity studies and X-ray structural insights will further enable development of GRK5 inhibitor-based new treatments against cancer and heart diseases.
{"title":"Potent and selective G protein-coupled receptor kinase 5 inhibitors: Design, synthesis, evaluation, and X-ray structural studies","authors":"Arun K. Ghosh , Rajesh Manda , Ranjith Kumar Gadi , Yueyi Chen , Natalie M. Galvan , John J.G. Tesmer","doi":"10.1016/j.ejmech.2025.118393","DOIUrl":"10.1016/j.ejmech.2025.118393","url":null,"abstract":"<div><div>We report here design of a series of highly selective, potent, non-covalent, and drug-like G protein-coupled receptor kinase 5 (GRK5) inhibitors. GRK5 is an important target for drug development for potential treatment of heart failure and cancer. Utilizing pyrroloindolinone as the main scaffold, which is embedded in the FDA-approved, orally bioavailable anti-cancer drug, sunitinib, we used structure-based design to generate a series of noncovalent, and drug-like GRK5 inhibitors. Several compounds exhibited low nanomolar potency and high selectivity against the related kinase GRK2. Three high-resolution X-ray crystal structures of GRK5-inhibitor complexes were determined to obtain insights into the ligand-binding site interactions. The current structure-activity studies and X-ray structural insights will further enable development of GRK5 inhibitor-based new treatments against cancer and heart diseases.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118393"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
New conjugates of an anticholinesterase drug, amiridine, linked to vitamin B6 derivatives pyridoximines 3 and pyridoxamines 4 with different lengths of alkylene spacers, were synthesized and assessed as potential multifunctional anti-Alzheimer's disease (anti-AD) agents. All conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC50: AChE, 0.386–2.53 μM; BChE, 0.031–1.45 μM), but poor activity against off-target carboxylesterase. Conjugates were mixed-type reversible inhibitors of AChE and BChE and displaced propidium from the AChE peripheral anionic site at the level of donepezil. All conjugates inhibited Aβ42 self-aggregation in the thioflavin test, wherein conjugates 3 were more active; inhibition increased with spacer elongation, being greatest for (CH2)8. Results agreed with molecular docking to AChE, BChE and Aβ42. Conjugates exhibited high ABTS•+-scavenging activity comparable to Trolox and the starting pyridoxal. Moreover, compounds 4 were three times more active than their imine analogues 3, which agreed with quantum chemical analysis. Using the example of imine 3c, the possibility of conjugates of this type to bind biogenic metal ions was shown by UV–Vis spectroscopy. Pyridoxamines 4a,b with spacers n = 4,6 were less toxic in general than imines 3a,b toward HEK293T, HepG2, and SHY5Y cell lines. Additionally, conjugates demonstrated neuroprotection in models of hydrogen peroxide and glutamate-induced oxidative stress in neuroblastoma SH-SY5Y cells, where compounds 4a,b were more active than 3a,b. Altogether, the results indicated that the new conjugates possessed potential for further development as multifunctional anti-AD drug candidates.
{"title":"Synthesis, biological evaluation, and in silico studies of pyridoxal–amiridine hybrids as multitargeting anti-Alzheimer's disease agents","authors":"G.F. Makhaeva , M.V. Grishchenko , E.V. Rudakova , N.V. Kovaleva , N.P. Boltneva , T.S. Skornyakova , O.G. Khudina , E.V. Shchegolkov , E.F. Zhilina , T.Yu. Astakhova , P.G. Pronkin , E.N. Timokhina , M.A. Lapshina , E.S. Dubrovskaya , E.V. Radchenko , V.A. Palyulin , Ya.V. Burgart , V.I. Saloutin , V.N. Charushin , R.J. Richardson","doi":"10.1016/j.ejmech.2025.118397","DOIUrl":"10.1016/j.ejmech.2025.118397","url":null,"abstract":"<div><div>New conjugates of an anticholinesterase drug, amiridine, linked to vitamin B6 derivatives pyridoximines <strong>3</strong> and pyridoxamines <strong>4</strong> with different lengths of alkylene spacers, were synthesized and assessed as potential multifunctional anti-Alzheimer's disease (anti-AD) agents. All conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC<sub>50</sub>: AChE, 0.386–2.53 μM; BChE, 0.031–1.45 μM), but poor activity against off-target carboxylesterase. Conjugates were mixed-type reversible inhibitors of AChE and BChE and displaced propidium from the AChE peripheral anionic site at the level of donepezil. All conjugates inhibited Aβ<sub>42</sub> self-aggregation in the thioflavin test, wherein conjugates <strong>3</strong> were more active; inhibition increased with spacer elongation, being greatest for (CH<sub>2</sub>)<sub>8</sub>. Results agreed with molecular docking to AChE, BChE and Aβ<sub>42</sub>. Conjugates exhibited high ABTS<sup>•+</sup>-scavenging activity comparable to Trolox and the starting pyridoxal. Moreover, compounds <strong>4</strong> were three times more active than their imine analogues <strong>3</strong>, which agreed with quantum chemical analysis. Using the example of imine <strong>3c</strong>, the possibility of conjugates of this type to bind biogenic metal ions was shown by UV–Vis spectroscopy. Pyridoxamines <strong>4a</strong>,<strong>b</strong> with spacers n = 4,6 were less toxic in general than imines <strong>3a</strong>,<strong>b</strong> toward HEK293T, HepG2, and SHY5Y cell lines. Additionally, conjugates demonstrated neuroprotection in models of hydrogen peroxide and glutamate-induced oxidative stress in neuroblastoma SH-SY5Y cells, where compounds <strong>4a,b</strong> were more active than <strong>3a</strong>,<strong>b</strong>. Altogether, the results indicated that the new conjugates possessed potential for further development as multifunctional anti-AD drug candidates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118397"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.ejmech.2025.118409
Xinli Du , Xuyan Liu , Lei Li , Zijin Feng , Yisheng Zhong , Kun Luo , Zhijing Hu , Peng Xie , Guan Wang
Parkinson's disease (PD) patients cause substantial motor impairment in daily life, with approximately 40 % patients also exhibiting comorbid depression. Current therapy predominantly employs dopamine D2R/D3R agonists, whereas 5-HT1AR activation confers clinically validated antidepressant benefits. Therefore, in this study, we report the discovery of compound 22b, a D2R/D3R/5-HT1AR muti-target agonist, which demonstrates both enhanced antiparkinsonian and antidepressant-like activities. A new series of 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives were designed, synthesized, and evaluated for receptor activity and hERG inhibition. Among them, compound 22b showed potent agonistic activity at D2R (EC50 = 1.29 nM), D3R (EC50 = 1.05 nM) and 5-HT1AR (EC50 = 153.50 nM), with favorable metabolic stability (T1/2p.o. = 3.77 h), neuroprotective effects and blood-brain barrier permeability (B/P = 0.348–0.506). In vivo, 22b significantly improved total distance traveled in MPTP-induced PD mouse models at 3 mg/kg (s.c.) and depressive-like behaviors in forced swim test in mice at low doses (1 mg/kg p.o.). These findings highlight 22b as a promising candidate for future exploration aiming at treatment of depression and Parkinson's disease.
{"title":"Novel 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives as triple-target D2R/D3R/5-HT1AR agonists with robust antidepressant and antiparkinsonian activity","authors":"Xinli Du , Xuyan Liu , Lei Li , Zijin Feng , Yisheng Zhong , Kun Luo , Zhijing Hu , Peng Xie , Guan Wang","doi":"10.1016/j.ejmech.2025.118409","DOIUrl":"10.1016/j.ejmech.2025.118409","url":null,"abstract":"<div><div>Parkinson's disease (PD) patients cause substantial motor impairment in daily life, with approximately 40 % patients also exhibiting comorbid depression. Current therapy predominantly employs dopamine D<sub>2</sub>R/D<sub>3</sub>R agonists, whereas 5-HT<sub>1A</sub>R activation confers clinically validated antidepressant benefits. Therefore, in this study, we report the discovery of compound <strong>22b,</strong> a D<sub>2</sub>R/D<sub>3</sub>R/5-HT<sub>1A</sub>R muti-target agonist, which demonstrates both enhanced antiparkinsonian and antidepressant-like activities. A new series of 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives were designed, synthesized, and evaluated for receptor activity and hERG inhibition. Among them, compound <strong>22b</strong> showed potent agonistic activity at D<sub>2</sub>R (EC<sub>50</sub> = 1.29 nM), D<sub>3</sub>R (EC<sub>50</sub> = 1.05 nM) and 5-HT<sub>1A</sub>R (EC<sub>50</sub> = 153.50 nM), with favorable metabolic stability (T<sub>1/2p.o.</sub> = 3.77 h), neuroprotective effects and blood-brain barrier permeability (B/P = 0.348–0.506). In vivo, <strong>22b</strong> significantly improved total distance traveled in MPTP-induced PD mouse models at 3 mg/kg (s.c.) and depressive-like behaviors in forced swim test in mice at low doses (1 mg/kg p.o.). These findings highlight <strong>22b</strong> as a promising candidate for future exploration aiming at treatment of depression and Parkinson's disease.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118409"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.ejmech.2025.118406
Zhi Gong , Ruixue Zhang , Linpu Yang , Hongzhi Gong , Chao Huang , Xiaohong Yang , Haibo Peng , Yun He
The promising antibiotic mupirocin suffers from rapid enzymatic degradation in plasma, characterized by an extremely short half-life, which strictly limits its use to topical applications. To overcome this pharmacokinetic limitation, we rationally designed mupirocin prodrugs targeting its carboxylic acid with enzymatically cleavable ester linkers. The synthesis was achieved through a selective esterification reaction of the mupirocin's carboxyl group with various lipophilic moieties. All newly synthesized prodrug candidates were fully characterized using 1H NMR, 13C NMR, and HRMS. The lead compound 3d, featuring a cholesterol-disulfide linker, demonstrated optimized pharmacokinetic properties with a 6-fold extended plasma half-life and a remarkable 1356-fold greater pulmonary area under the concentration-time curve (AUC) compared to mupirocin. In both systemic and neutropenic murine lung infection models, 3d exhibited potent anti-MRSA efficacy (50–100 mg/kg). This study validates the prodrug approach as a viable strategy to unlock the systemic therapeutic potential of mupirocin against bacterial infections.
{"title":"Design, synthesis, and evaluation of mupirocin prodrugs restoring systemic efficacy against MRSA","authors":"Zhi Gong , Ruixue Zhang , Linpu Yang , Hongzhi Gong , Chao Huang , Xiaohong Yang , Haibo Peng , Yun He","doi":"10.1016/j.ejmech.2025.118406","DOIUrl":"10.1016/j.ejmech.2025.118406","url":null,"abstract":"<div><div>The promising antibiotic mupirocin suffers from rapid enzymatic degradation in plasma, characterized by an extremely short half-life, which strictly limits its use to topical applications. To overcome this pharmacokinetic limitation, we rationally designed mupirocin prodrugs targeting its carboxylic acid with enzymatically cleavable ester linkers. The synthesis was achieved through a selective esterification reaction of the mupirocin's carboxyl group with various lipophilic moieties. All newly synthesized prodrug candidates were fully characterized using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HRMS. The lead compound <strong>3d</strong>, featuring a cholesterol-disulfide linker, demonstrated optimized pharmacokinetic properties with a 6-fold extended plasma half-life and a remarkable 1356-fold greater pulmonary area under the concentration-time curve (AUC) compared to mupirocin. In both systemic and neutropenic murine lung infection models, <strong>3d</strong> exhibited potent anti-MRSA efficacy (50–100 mg/kg). This study validates the prodrug approach as a viable strategy to unlock the systemic therapeutic potential of mupirocin against bacterial infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118406"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.ejmech.2025.118390
Isabel Mª Calero-Docina , Samuel Delgado-Hernández , Sophie Luis-Rancel , Carlos J. Bethencourt-Estrella , Sergio J. Álvarez-Méndez , Atteneri López-Arencibia , Jacob Lorenzo-Morales , José E. Piñero
Leishmaniasis and Chagas disease are parasitic infections with limited treatment options due to drug toxicity and rising resistance. Leishmaniasis, caused by Leishmania spp., often manifests in a cutaneous form and is treated with drugs like amphotericin B and miltefosine, which can cause severe side effects. Chagas disease, caused by Trypanosoma cruzi, is endemic in the Americas and classified by the WHO as a neglected tropical disease. Existing treatments are effective mainly in the acute phase but have significant limitations. In search of new therapies, this study explored diversity-oriented synthesis to generate a library of β,γ-unsaturated carboxylic acid derivatives. From 23 synthesized compounds −12 reported for the first time– several showed promising antiparasitic activity. Four compounds were effective against Leishmania amazonensis, with three also targeting the amastigote form. Two compounds showed activity against Trypanosoma cruzi, outperforming reference drugs in selectivity. Signs of parasite apoptosis, including mitochondrial damage and ROS accumulation, suggest strong therapeutic potential for these derivatives.
{"title":"Leishmanicidal and trypanocidal potential of ß,γ-unsaturated carboxylic acid synthetic derivatives","authors":"Isabel Mª Calero-Docina , Samuel Delgado-Hernández , Sophie Luis-Rancel , Carlos J. Bethencourt-Estrella , Sergio J. Álvarez-Méndez , Atteneri López-Arencibia , Jacob Lorenzo-Morales , José E. Piñero","doi":"10.1016/j.ejmech.2025.118390","DOIUrl":"10.1016/j.ejmech.2025.118390","url":null,"abstract":"<div><div>Leishmaniasis and Chagas disease are parasitic infections with limited treatment options due to drug toxicity and rising resistance. Leishmaniasis, caused by <em>Leishmania</em> spp., often manifests in a cutaneous form and is treated with drugs like amphotericin B and miltefosine, which can cause severe side effects. Chagas disease, caused by <em>Trypanosoma cruzi</em>, is endemic in the Americas and classified by the WHO as a neglected tropical disease. Existing treatments are effective mainly in the acute phase but have significant limitations. In search of new therapies, this study explored diversity-oriented synthesis to generate a library of β,γ-unsaturated carboxylic acid derivatives. From 23 synthesized compounds −12 reported for the first time– several showed promising antiparasitic activity. Four compounds were effective against <em>Leishmania amazonensis</em>, with three also targeting the amastigote form. Two compounds showed activity against <em>Trypanosoma cruzi</em>, outperforming reference drugs in selectivity. Signs of parasite apoptosis, including mitochondrial damage and ROS accumulation, suggest strong therapeutic potential for these derivatives.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118390"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.ejmech.2025.118407
Suntao Shi , Jingwen Tu , Miao Zhong , Jiahui Xi , Junlei Hao , Ziyi Wu , Haijuan Zhang , Zhongtian Bai , Baoxin Zhang
Thioredoxin reductase (TrxR) is a critical enzyme in maintaining cellular redox balance, and its inhibition has emerged as a promising anticancer strategy by compromising the antioxidant capacity of tumor cells and inducing oxidative stress-mediated apoptosis. In our previous work, we identified PAO-PDT as a highly potent organoarsenic TrxR inhibitor, revealing a novel mode of TrxR inhibition at nanomolar concentrations. Building on this discovery, we aim to augment the antitumor efficacy of organoarsenic compounds by incorporating cinnamic acid, a naturally occurring compound derived from cinnamon, which has been reported to exhibit potent anticancer activity. A series of CA-conjugated organoarsenic derivatives were rationally designed and synthesized. After preliminary screening, As-CA11 demonstrated potent antiproliferative activity against HL-60 cells (IC50 = 0.28 ± 0.05 μM) and exhibited strong inhibition of TrxR in vitro (IC50 = 18.7 ± 0.02 nM). Mechanistic investigations revealed that As-CA11 promotes intracellular ROS accumulation through TrxR inhibition, thereby disrupting redox homeostasis and inducing apoptosis. These effects were further confirmed in a 4T1 tumor-bearing mouse model. Collectively, our results highlight the potential of structurally modifying organoarsenic scaffolds with bioactive natural product moieties to improve antitumor efficacy, offering promising leads for the development of next-generation organoarsenic-based therapeutics.
{"title":"Structure-Guided optimization of PAO-PDT yields TrxR inhibitors as potential anticancer agent","authors":"Suntao Shi , Jingwen Tu , Miao Zhong , Jiahui Xi , Junlei Hao , Ziyi Wu , Haijuan Zhang , Zhongtian Bai , Baoxin Zhang","doi":"10.1016/j.ejmech.2025.118407","DOIUrl":"10.1016/j.ejmech.2025.118407","url":null,"abstract":"<div><div>Thioredoxin reductase (TrxR) is a critical enzyme in maintaining cellular redox balance, and its inhibition has emerged as a promising anticancer strategy by compromising the antioxidant capacity of tumor cells and inducing oxidative stress-mediated apoptosis. In our previous work, we identified <strong>PAO-PDT</strong> as a highly potent organoarsenic TrxR inhibitor, revealing a novel mode of TrxR inhibition at nanomolar concentrations. Building on this discovery, we aim to augment the antitumor efficacy of organoarsenic compounds by incorporating cinnamic acid, a naturally occurring compound derived from cinnamon, which has been reported to exhibit potent anticancer activity. A series of CA-conjugated organoarsenic derivatives were rationally designed and synthesized. After preliminary screening, <strong>As-CA11</strong> demonstrated potent antiproliferative activity against HL-60 cells (IC<sub>50</sub> = 0.28 ± 0.05 μM) and exhibited strong inhibition of TrxR <em>in vitro</em> (IC<sub>50</sub> = 18.7 ± 0.02 nM). Mechanistic investigations revealed that <strong>As-CA11</strong> promotes intracellular ROS accumulation through TrxR inhibition, thereby disrupting redox homeostasis and inducing apoptosis. These effects were further confirmed in a 4T1 tumor-bearing mouse model. Collectively, our results highlight the potential of structurally modifying organoarsenic scaffolds with bioactive natural product moieties to improve antitumor efficacy, offering promising leads for the development of next-generation organoarsenic-based therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118407"},"PeriodicalIF":5.9,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.ejmech.2025.118403
Xiaolong Ye , Shengzhe Deng , Ding Luo , Wanghong Fu , Qingqing Du , Weiwei Xue
The dopamine transporter (DAT) is a pivotal target in the management of central nervous system (CNS) disorders. Existing drugs that competitively bind to the orthosteric site on DAT are associated with several side effects. Although the concept of allostery in DAT has been acknowledged for years, the precise allosteric sites remain elusive, impeding the rational design of allosteric modulators for DAT. In this study, we utilized a conformation-guided strategy to discover new allosteric modulators for the human DAT (hDAT). Starting with the recently reported cryo-EM structure of hDAT in the occluded (OC) state, several potential allosteric sites were mapped on the transporter. Then, a druggable pocket located at the extracellular vestibule was selected to perform virtual screening against four Enamine libraries (106,083 compounds), which led to the selection of four compounds for fluorescence-based substrate uptake assays. Among these, Z236004662 (DAM-001) from Enamine CNS Library was found as a new allosteric inhibitor of hDAT with an IC50 of 24.70 [6.472; 153.2] μM and 1.026 [0.616; 1.769] μM in the absence and presence of orthosteric inhibitor nomifensine. Further comprehensive molecular dynamics (MD) simulations and end-point binding free energy analysis were conducted to elucidate the synergistic effect of DAM-001 and nomifensine on hDAT allosteric inhibition. Additional supervised MD (SuMD) was used to reveal the specific recognition and spontaneously binding pathways of DAM-001 to the allosteric site on hDAT. This work demonstrates the potential of our method for identifying new allosteric modulators for related therapeutic targets.
{"title":"Discovery of a new allosteric inhibitor for human dopamine transporter by physics-based modeling and experimental validation","authors":"Xiaolong Ye , Shengzhe Deng , Ding Luo , Wanghong Fu , Qingqing Du , Weiwei Xue","doi":"10.1016/j.ejmech.2025.118403","DOIUrl":"10.1016/j.ejmech.2025.118403","url":null,"abstract":"<div><div>The dopamine transporter (DAT) is a pivotal target in the management of central nervous system (CNS) disorders. Existing drugs that competitively bind to the orthosteric site on DAT are associated with several side effects. Although the concept of allostery in DAT has been acknowledged for years, the precise allosteric sites remain elusive, impeding the rational design of allosteric modulators for DAT. In this study, we utilized a conformation-guided strategy to discover new allosteric modulators for the human DAT (hDAT). Starting with the recently reported cryo-EM structure of hDAT in the occluded (OC) state, several potential allosteric sites were mapped on the transporter. Then, a druggable pocket located at the extracellular vestibule was selected to perform virtual screening against four Enamine libraries (106,083 compounds), which led to the selection of four compounds for fluorescence-based substrate uptake assays. Among these, Z236004662 (DAM-001) from Enamine CNS Library was found as a new allosteric inhibitor of hDAT with an IC<sub>50</sub> of 24.70 [6.472; 153.2] μM and 1.026 [0.616; 1.769] μM in the absence and presence of orthosteric inhibitor nomifensine. Further comprehensive molecular dynamics (MD) simulations and end-point binding free energy analysis were conducted to elucidate the synergistic effect of DAM-001 and nomifensine on hDAT allosteric inhibition. Additional supervised MD (SuMD) was used to reveal the specific recognition and spontaneously binding pathways of DAM-001 to the allosteric site on hDAT. This work demonstrates the potential of our method for identifying new allosteric modulators for related therapeutic targets.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118403"},"PeriodicalIF":5.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this study, a series of novel small molecule Rac1 inhibitors were rationally designed and synthesized by targeting key pharmacophore features associated with its hydrophobic pocket. Structural confirmation of the compounds was achieved through spectral analysis, and their cytotoxic effects were evaluated using MTT test on breast cancer and healthy breast epithelial cell lines. Cytotoxicity screening revealed six compounds as the most active and selective, with IC50 values ranging from 9 to 19 μM and selectivity indexes greater than 2.9 based on the MTT assay. Further evaluation using a Rac1 inhibition assay demonstrated that two compounds bearing 2-fluorophenyl and 4-methylphenyl substituents exhibited the strongest inhibitory effects, with 81 % and 78 % inhibition at 19 μM and 12 μM, respectively, whereas NSC23766, a reported selective Rac1 inhibitor, showed 82 % activity at 100 μM. At their IC50 concentrations, both compounds induced apoptosis in MCF-7 cells. A structure–activity relationship analysis was conducted to elucidate the correlation between specific structural modifications and biological activity. The strong agreement between docking scores and biological assay data supports the conclusion that these two compounds act as potent inhibitors of Rac1-GEF interaction, thereby interfering with Rac1-mediated oncogenic signaling. Given their strong in vitro activity and favorable selectivity, these compounds are proposed as promising hit candidates for further in vivo studies to evaluate their therapeutic potential and safety profiles.
{"title":"Design, synthesis and evaluation of novel oxadiazole-based compounds as potential Rac1 inhibitors against breast cancer","authors":"Ayca Erdogan , Dilruba Tirpanlar , Burcin Gungor , Enise Ece Gurdal , Wolfgang Sippl , Basak Aru , Gulderen Yanikkaya Demirel , Meric Koksal","doi":"10.1016/j.ejmech.2025.118396","DOIUrl":"10.1016/j.ejmech.2025.118396","url":null,"abstract":"<div><div>In this study, a series of novel small molecule Rac1 inhibitors were rationally designed and synthesized by targeting key pharmacophore features associated with its hydrophobic pocket. Structural confirmation of the compounds was achieved through spectral analysis, and their cytotoxic effects were evaluated using MTT test on breast cancer and healthy breast epithelial cell lines. Cytotoxicity screening revealed six compounds as the most active and selective, with IC<sub>50</sub> values ranging from 9 to 19 μM and selectivity indexes greater than 2.9 based on the MTT assay. Further evaluation using a Rac1 inhibition assay demonstrated that two compounds bearing 2-fluorophenyl and 4-methylphenyl substituents exhibited the strongest inhibitory effects, with 81 % and 78 % inhibition at 19 μM and 12 μM, respectively, whereas NSC23766, a reported selective Rac1 inhibitor, showed 82 % activity at 100 μM. At their IC<sub>50</sub> concentrations, both compounds induced apoptosis in MCF-7 cells. A structure–activity relationship analysis was conducted to elucidate the correlation between specific structural modifications and biological activity. The strong agreement between docking scores and biological assay data supports the conclusion that these two compounds act as potent inhibitors of Rac1-GEF interaction, thereby interfering with Rac1-mediated oncogenic signaling. Given their strong <em>in vitro</em> activity and favorable selectivity, these compounds are proposed as promising hit candidates for further <em>in vivo</em> studies to evaluate their therapeutic potential and safety profiles.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"303 ","pages":"Article 118396"},"PeriodicalIF":5.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.ejmech.2025.118401
Alam Zeb , Salim Al-Babili
Crocetin is an important naturally occurring substance that belongs to the carotenoids and is produced by few plant species. Among these plants, Crocus sativus (Saffron) is a rich source of crocetin and its conjugated compounds known as crocins. While crocins have been extensively studied in Saffron, crocetin has received less attention in the literature. Existing reviews reported on crocetin alone have been mixed with crocins and lack sufficient detail for full comprehension. Therefore, a comprehensive review is needed to clarify our understanding of the available information on crocetin. This review explores the detailed chemistry of crocetin, its biosynthetic pathways, bioengineering, and mechanism of pharmacological actions based on latest scientific findings. Pharmacological actions discussed include findings from in-vitro, in-vivo, and human studies. In in-vitro studies, crocetin has shown anti-cancer, cardio-protective, and antioxidant properties against oxidative stress. In in-vivo studies, crocetin has demonstrated cardio-protective, neuroprotective, oxidative stress, anti-diabetic, and anti-cancer effects. Limited clinical trials reported, highlighting the need for further large-scale human trials to confirm these actions. In conclusion, crocetin is a versatile compound with significant potential for future medicinal research and applications.
{"title":"Chemistry, biochemistry, and mechanism of pharmacological actions of crocetin","authors":"Alam Zeb , Salim Al-Babili","doi":"10.1016/j.ejmech.2025.118401","DOIUrl":"10.1016/j.ejmech.2025.118401","url":null,"abstract":"<div><div>Crocetin is an important naturally occurring substance that belongs to the carotenoids and is produced by few plant species. Among these plants, <em>Crocus sativus</em> (Saffron) is a rich source of crocetin and its conjugated compounds known as crocins. While crocins have been extensively studied in Saffron, crocetin has received less attention in the literature. Existing reviews reported on crocetin alone have been mixed with crocins and lack sufficient detail for full comprehension. Therefore, a comprehensive review is needed to clarify our understanding of the available information on crocetin. This review explores the detailed chemistry of crocetin, its biosynthetic pathways, bioengineering, and mechanism of pharmacological actions based on latest scientific findings. Pharmacological actions discussed include findings from in-vitro, in-vivo, and human studies. In in-vitro studies, crocetin has shown anti-cancer, cardio-protective, and antioxidant properties against oxidative stress. In in-vivo studies, crocetin has demonstrated cardio-protective, neuroprotective, oxidative stress, anti-diabetic, and anti-cancer effects. Limited clinical trials reported, highlighting the need for further large-scale human trials to confirm these actions. In conclusion, crocetin is a versatile compound with significant potential for future medicinal research and applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"302 ","pages":"Article 118401"},"PeriodicalIF":5.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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