The rise of drug-resistant tuberculosis (TB) has created an urgent need to discover and develop new anti-mycobacterial agents. Herein, we report the synthesis and evaluation of a library of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides as promising anti-TB agents. In preliminary screening, 10 out of 26 compounds displayed potent in vitro inhibition against Mtb H37Rv with a MIC value of 0.03 μg/mL, which is 17-fold more potent than the first-line TB drug streptomycin, 33-fold more potent than ethambutol, and equipotent with isoniazid and rifampicin. Encouragingly, most of these compounds exhibited a selectivity index (SI) >3333.3 and CC₅₀ values >100 μg/mL against Vero cells, indicating they are over 3000 times more toxic to M. tuberculosis than to mammalian cells and demonstrate absence of cytotoxicity at concentrations effective against TB (MIC = 0.03 μg/mL). Among them, 12a, 14a, and 14d demonstrated remarkable activity against drug-resistant strains of Mtb with an MIC of 0.03 μM. Time-kill kinetic studies revealed that 12a, 14a, and 14d exhibited bacteriostatic properties. Furthermore, 12a, 14a, and 14d demonstrated synergistic effects with the FDA-approved anti-TB drugs rifampicin (ƩFIC 0.093), ethambutol (ƩFIC 0.061), and moxifloxacin (ƩFIC 0.154-0.281), exhibiting bactericidal time-kill properties in combination with these drugs. Additionally, 12a, 14a, and 14d exhibited acceptable metabolic stability (CLint 11.49-14.62 μL/min/mg microsomal protein), indicating effective drug levels and bioavailability. Also, 12a, 14a, and 14d showed stable interactions with QcrB in docking studies. These findings highlight 12a, 14a, and 14d as potential candidates for in vivo evaluation and further development as novel anti-tubercular drugs.
{"title":"Synthesis of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides and evaluation of their antitubercular activity.","authors":"Ojaswitha Ommi, Harshada Anil Bhalerao, Pradip Malik, Juned Ali, Deepanshi Saxena, Srinivas Nanduri, Rajesh Sonti, Arunava Dasgupta, Sidharth Chopra, Venkata Madhavi Yaddanapudi","doi":"10.1016/j.bmc.2025.118341","DOIUrl":"10.1016/j.bmc.2025.118341","url":null,"abstract":"<p><p>The rise of drug-resistant tuberculosis (TB) has created an urgent need to discover and develop new anti-mycobacterial agents. Herein, we report the synthesis and evaluation of a library of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides as promising anti-TB agents. In preliminary screening, 10 out of 26 compounds displayed potent in vitro inhibition against Mtb H37Rv with a MIC value of 0.03 μg/mL, which is 17-fold more potent than the first-line TB drug streptomycin, 33-fold more potent than ethambutol, and equipotent with isoniazid and rifampicin. Encouragingly, most of these compounds exhibited a selectivity index (SI) >3333.3 and CC₅₀ values >100 μg/mL against Vero cells, indicating they are over 3000 times more toxic to M. tuberculosis than to mammalian cells and demonstrate absence of cytotoxicity at concentrations effective against TB (MIC = 0.03 μg/mL). Among them, 12a, 14a, and 14d demonstrated remarkable activity against drug-resistant strains of Mtb with an MIC of 0.03 μM. Time-kill kinetic studies revealed that 12a, 14a, and 14d exhibited bacteriostatic properties. Furthermore, 12a, 14a, and 14d demonstrated synergistic effects with the FDA-approved anti-TB drugs rifampicin (ƩFIC 0.093), ethambutol (ƩFIC 0.061), and moxifloxacin (ƩFIC 0.154-0.281), exhibiting bactericidal time-kill properties in combination with these drugs. Additionally, 12a, 14a, and 14d exhibited acceptable metabolic stability (CL<sub>int</sub> 11.49-14.62 μL/min/mg microsomal protein), indicating effective drug levels and bioavailability. Also, 12a, 14a, and 14d showed stable interactions with QcrB in docking studies. These findings highlight 12a, 14a, and 14d as potential candidates for in vivo evaluation and further development as novel anti-tubercular drugs.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118341"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bromodomain-containing protein 4 (BRD4), a crucial epigenetic regulator in cancer, has become a critical target for melanoma therapy. Herein, we investigated a strategy for enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. A compound that exhibits antitumor effects in a mouse melanoma xenograft model at doses lower than those required for previously reported compound 1 is required. Therefore, we focused on enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. Our hypothesis state that mitigating P-glycoprotein (P-gp) substrate recognition can improve cell permeability and enhance cellular inhibitory activity. Thus, we reduced the hydrogen-bond donors (HBDs) of a benzimidazole core through N-alkylation. Using this approach, we successfully enhanced the cellular inhibitory activity by mitigating P-gp substrate recognition; however, the compounds derived from this approach exhibited poor metabolic stability. To overcome this issue, we used a scaffold-hopping strategy to identify core-lacking HBDs and discovered the imidazopyridine derivative 17. This compound exhibits potent antiproliferative activity against melanoma cells and good oral exposure. Thus, we conclude that mitigation of P-gp substrate recognition can effectively enhance cellular activity and identify favorable antitumor agents.
{"title":"Discovering a potent and orally available imidazopyridine derivative as a BRD4 inhibitor: Enhancing antiproliferative activity against melanoma cells by mitigating P-gp substrate recognition.","authors":"Yuhei Horai, Naoki Suda, Shinsuke Uchihashi, Mayako Katakuse, Tomomi Shigeno, Takashige Hirano, Junichi Takahara, Tomoyuki Fujita, Yohei Mukoyama, Yuji Haga","doi":"10.1016/j.bmc.2025.118337","DOIUrl":"10.1016/j.bmc.2025.118337","url":null,"abstract":"<p><p>Bromodomain-containing protein 4 (BRD4), a crucial epigenetic regulator in cancer, has become a critical target for melanoma therapy. Herein, we investigated a strategy for enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. A compound that exhibits antitumor effects in a mouse melanoma xenograft model at doses lower than those required for previously reported compound 1 is required. Therefore, we focused on enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. Our hypothesis state that mitigating P-glycoprotein (P-gp) substrate recognition can improve cell permeability and enhance cellular inhibitory activity. Thus, we reduced the hydrogen-bond donors (HBDs) of a benzimidazole core through N-alkylation. Using this approach, we successfully enhanced the cellular inhibitory activity by mitigating P-gp substrate recognition; however, the compounds derived from this approach exhibited poor metabolic stability. To overcome this issue, we used a scaffold-hopping strategy to identify core-lacking HBDs and discovered the imidazopyridine derivative 17. This compound exhibits potent antiproliferative activity against melanoma cells and good oral exposure. Thus, we conclude that mitigation of P-gp substrate recognition can effectively enhance cellular activity and identify favorable antitumor agents.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118337"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.bmc.2025.118340
Yuqing Wei, Baichen Xiong, Zuoaoyun Song, Sheng Zhong, Na Zheng, Ao Zhang, Yao Chen, Haopeng Sun
Aging is a progressive degenerative state characterized by a gradual loss of physiological fitness, resulting in deteriorated functions and susceptibility to age-related diseases. With the progress of research on aging and age-related mechanisms, identifying effective anti-aging drugs has become a key focus. In this review, we summarize aging and its related signaling pathways and targets, mainly including clearance of senescent cells, NAD+ augmentation, anti-inflammatory and anti-oxidant defense, dysfunction of proteostasis and activation of telomerase. Furthermore, we collect advanced research progress of anti-aging agents and other strategies to delay aging and age-related diseases, and ultimately ameliorate lifespan and healthspan. Finally, we review anti-aging research and discuss potential strategies for aging intervention.
{"title":"Aging and anti-aging strategies: A review of past and future therapeutics.","authors":"Yuqing Wei, Baichen Xiong, Zuoaoyun Song, Sheng Zhong, Na Zheng, Ao Zhang, Yao Chen, Haopeng Sun","doi":"10.1016/j.bmc.2025.118340","DOIUrl":"10.1016/j.bmc.2025.118340","url":null,"abstract":"<p><p>Aging is a progressive degenerative state characterized by a gradual loss of physiological fitness, resulting in deteriorated functions and susceptibility to age-related diseases. With the progress of research on aging and age-related mechanisms, identifying effective anti-aging drugs has become a key focus. In this review, we summarize aging and its related signaling pathways and targets, mainly including clearance of senescent cells, NAD<sup>+</sup> augmentation, anti-inflammatory and anti-oxidant defense, dysfunction of proteostasis and activation of telomerase. Furthermore, we collect advanced research progress of anti-aging agents and other strategies to delay aging and age-related diseases, and ultimately ameliorate lifespan and healthspan. Finally, we review anti-aging research and discuss potential strategies for aging intervention.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118340"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-29DOI: 10.1016/j.bmc.2025.118335
Yu-Fan Zhou, Hui Xu, Dan-Yang Chen, Xi-Le Hu, Guo-Rong Chen, Tony D James, Xiao-Peng He
The exploitation of glycans as targeting agents to construct delivery materials has proved useful for targeted disease diagnosis and therapy. To achieve effective targeting, multivalent glycosides are prepared to enhance avidity with sugar receptors. In this study, we designed and synthesized a new trivalent mannoside (Man3-PEG3-N3) bearing an azido unit. This azido mannosyl glycocluster was used to conjugate with cyclooctyne-modified human serum albumin (HSA) through strain-promoted click chemistry. Mass spectroscopic analysis validated the successful construction of the glycocluster-conjugated HSA, and a fluorescence titration assay indicated that the resulting conjugate is capable of accommodating an environmentally sensitive dye.
{"title":"Click conjugation of trivalent mannosyl glycocluster with human serum albumin to generate a cell targeting delivery vehicle.","authors":"Yu-Fan Zhou, Hui Xu, Dan-Yang Chen, Xi-Le Hu, Guo-Rong Chen, Tony D James, Xiao-Peng He","doi":"10.1016/j.bmc.2025.118335","DOIUrl":"10.1016/j.bmc.2025.118335","url":null,"abstract":"<p><p>The exploitation of glycans as targeting agents to construct delivery materials has proved useful for targeted disease diagnosis and therapy. To achieve effective targeting, multivalent glycosides are prepared to enhance avidity with sugar receptors. In this study, we designed and synthesized a new trivalent mannoside (Man<sub>3</sub>-PEG<sub>3</sub>-N<sub>3</sub>) bearing an azido unit. This azido mannosyl glycocluster was used to conjugate with cyclooctyne-modified human serum albumin (HSA) through strain-promoted click chemistry. Mass spectroscopic analysis validated the successful construction of the glycocluster-conjugated HSA, and a fluorescence titration assay indicated that the resulting conjugate is capable of accommodating an environmentally sensitive dye.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118335"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1016/j.bmc.2025.118477
Mai S. El-Shoukrofy , Mai E. Amr , Tarek M. Okda , A.-Mohsen M.E. Omar , Omaima M. AboulWafa
Novel anti-breast cancer benzoxazoles were synthesized applying the scaffold hopping and molecular hybridization approaches. MTT assay showed that 6 and 9b were 4.5 and 2 times more potent than doxorubicin against MCF-7 cells, while 9a and 13b were 10 and 7.5 times more effective against MDA-MB-231 cells, respectively. The four compounds showed good safety profiles toward MCF-10A cells' growth. Enzyme inhibition assays identified 9b as a potent aromatase (ARO) inhibitor, exhibiting twice the potency of letrozole. 13d was more potent PI3Kα inhibitor than pictilisib, while 6, 9a, and 13b were multi-kinase inhibitors. Compound 9a was 2 and 2.5 times more potent than lapatinib against EGFRWT and EGFRL858R, besides being a selective PI3Kα/β inhibitor, surpassing pictilisib by 3 and 1.5 times, respectively. Compound 13b exhibited comparable EGFRL858R inhibition to lapatinib and outperformed pictilisib against PI3Kα, PI3Kβ, and PI3Kδ. Compound 6 showed greater ARO inhibition than letrozole, while being slightly less potent than pictilisib against PI3Kα and PI3Kβ. The four compounds downregulated p-ERK and/or p-AKT levels more effectively than letrozole or lapatinib. They elevated Beclin-1 levels and increased caspase-9 levels with 6, 9a and 9b inducing higher %total apoptosis than doxorubicin in annexin V/ propidium iodide assay. Moreover, 9a reduced cell migration and invasion percentages to 9.22 and 16.95 %, respectively, in MDA-MB-231-treated cells, thereby suppressed metastasis. Docking studies supported the in vitro enzymatic inhibition assays results. Thus, 9b and 13d are potent anti-breast cancer benzoxazoles with selective ARO and PI3kα inhibition activity, respectively, while 6, 9a, and 13b are multi-target inhibitors exhibiting other anticancer synergistic mechanisms.
{"title":"Novel benzoxazole-based hybrids as multi-target inhibitors of aromatase, EGFR, and PI3K with potential anti-breast cancer activity","authors":"Mai S. El-Shoukrofy , Mai E. Amr , Tarek M. Okda , A.-Mohsen M.E. Omar , Omaima M. AboulWafa","doi":"10.1016/j.bmc.2025.118477","DOIUrl":"10.1016/j.bmc.2025.118477","url":null,"abstract":"<div><div>Novel anti-breast cancer benzoxazoles were synthesized applying the scaffold hopping and molecular hybridization approaches. MTT assay showed that <strong>6</strong> and <strong>9b</strong> were 4.5 and 2 times more potent than doxorubicin against MCF-7 cells, while <strong>9a</strong> and <strong>13b</strong> were 10 and 7.5 times more effective against MDA-MB-231 cells, respectively. The four compounds showed good safety profiles toward MCF-10A cells' growth. Enzyme inhibition assays identified <strong>9b</strong> as a potent aromatase (ARO) inhibitor, exhibiting twice the potency of letrozole. <strong>13d</strong> was more potent PI3Kα inhibitor than pictilisib, while <strong>6, 9a,</strong> and <strong>13b</strong> were multi-kinase inhibitors. Compound <strong>9a</strong> was 2 and 2.5 times more potent than lapatinib against EGFR<sup>WT</sup> and EGFR<sup>L858R</sup>, besides being a selective PI3Kα/β inhibitor, surpassing pictilisib by 3 and 1.5 times, respectively. Compound <strong>13b</strong> exhibited comparable EGFR<sup>L858R</sup> inhibition to lapatinib and outperformed pictilisib against PI3Kα, PI3Kβ, and PI3Kδ. Compound <strong>6</strong> showed greater ARO inhibition than letrozole, while being slightly less potent than pictilisib against PI3Kα and PI3Kβ. The four compounds downregulated p-ERK and/or p-AKT levels more effectively than letrozole or lapatinib. They elevated Beclin-1 levels and increased caspase-9 levels with <strong>6, 9a</strong> and <strong>9b</strong> inducing higher %total apoptosis than doxorubicin in annexin V/ propidium iodide assay. Moreover, <strong>9a</strong> reduced cell migration and invasion percentages to 9.22 and 16.95 %, respectively, in MDA-MB-231-treated cells, thereby suppressed metastasis. Docking studies supported the <em>in vitro</em> enzymatic inhibition assays results. Thus, <strong>9b</strong> and <strong>13d</strong> are potent anti-breast cancer benzoxazoles with selective ARO and PI3kα inhibition activity, respectively, while <strong>6, 9a,</strong> and <strong>13b</strong> are multi-target inhibitors exhibiting other anticancer synergistic mechanisms.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118477"},"PeriodicalIF":3.0,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1016/j.bmc.2025.118475
Vitória Gaspar Bernardo , Rodrigo Santos Aquino de Araújo , Natália Barbosa de Mélo , Ricardo Eduardo Pereira Coutinho , Julyanne Maria Saraiva de Sousa , Maria Gabrielly Gonçalves da Silva Sousa , Natália Ferreira de Sousa , Wadja Feitosa dos Santos Silva , Paulo Fernando da Silva Santos-Júnior , Teresinha Gonçalves da Silva , Eduardo René Pérez González , Edeildo Ferreira da Silva Junior , Marcus Tullius Scotti , Anuraj Nayarisseri , Klinger Antonio da Franca Rodrigues , Francisco Jaime Bezerra Mendonça-Junior
Leishmaniasis is a neglected tropical disease with limited and often toxic treatment options. This study explores the antileishmanial potential of N-substituted thieno[2,3-c]pyridine derivatives through combined in vitro and in silico approaches. Initially, N-Boc-thieno[2,3-c]pyridine (2a–i) and N-Boc-thieno[2,3-b]pyridine (1a–f) derivatives were synthesized and evaluated against Leishmania amazonensis, L. braziliensis, L. infantum, and RAW 264.7 macrophages. Only N-Boc-thieno[2,3-c]pyridine derivatives with substituted nitrogen at position 6 (2b, 2c, 2f, 2g) were active (IC₅₀ < 10 μM). Based on this, a series of N-benzyl-thieno[2,3-c]pyridine analogs (3a–i) was synthesized, with compounds 3c, 3f, and 3g showing improved antipromastigote activity and selectivity índices (SI). Notably, compound 3f demonstrated potent amastigote activities (IC₅₀ between 0.83 and 1.13 μM), comparable to amphotericin B, but with a 250-fold higher SI and low in vivo toxicity (LD₅₀ = 2000 mg/kg in Zophobas morio). Physicochemical and pharmacokinetic predictions using SwissADME and Osiris indicated favorable drug-like properties and oral bioavailability for 3f. Molecular docking and dynamics simulations revealed strong binding affinities to Nucleoside Diphosphate Kinase (NDK) (PDB: 5GO1), Dihydroorotate Dehydrogenase (DHODH) (PDB: 4WZH), and Sterol 14α-Demethylase (CYP51) (PDB: 3L4D), surpassing reference ligands, with stable complexes, key catalytic site interactions, low RMSD, compact Radius of gyration, and reduced RMSF, supporting their potential as conformationally stable and specific enzyme inhibitors for leishmaniasis treatment. Altogether, these findings strongly highlight the potential of N-substituted thieno[2,3-c]pyridine as promising scaffolds for antileishmanial drug development and highlight compound 3f as a lead candidate for further optimization.
{"title":"Drug design and synthesis of new N-substituted-thienopyridine based on 2-aminothiophene derivatives as antileishmanial agents","authors":"Vitória Gaspar Bernardo , Rodrigo Santos Aquino de Araújo , Natália Barbosa de Mélo , Ricardo Eduardo Pereira Coutinho , Julyanne Maria Saraiva de Sousa , Maria Gabrielly Gonçalves da Silva Sousa , Natália Ferreira de Sousa , Wadja Feitosa dos Santos Silva , Paulo Fernando da Silva Santos-Júnior , Teresinha Gonçalves da Silva , Eduardo René Pérez González , Edeildo Ferreira da Silva Junior , Marcus Tullius Scotti , Anuraj Nayarisseri , Klinger Antonio da Franca Rodrigues , Francisco Jaime Bezerra Mendonça-Junior","doi":"10.1016/j.bmc.2025.118475","DOIUrl":"10.1016/j.bmc.2025.118475","url":null,"abstract":"<div><div>Leishmaniasis is a neglected tropical disease with limited and often toxic treatment options. This study explores the antileishmanial potential of <em>N</em>-substituted thieno[2,3-<em>c</em>]pyridine derivatives through combined <em>in vitro</em> and <em>in silico</em> approaches. Initially, <em>N</em>-Boc-thieno[2,3-<em>c</em>]pyridine (<strong>2a–i</strong>) and <em>N</em>-Boc-thieno[2,3-<em>b</em>]pyridine (<strong>1a–f</strong>) derivatives were synthesized and evaluated against <em>Leishmania amazonensis</em>, <em>L. braziliensis</em>, <em>L. infantum</em>, and RAW 264.7 macrophages. Only <em>N</em>-Boc-thieno[2,3-<em>c</em>]pyridine derivatives with substituted nitrogen at position 6 (<strong>2b</strong>, <strong>2c</strong>, <strong>2f</strong>, <strong>2g</strong>) were active (IC₅₀ < 10 μM). Based on this, a series of <em>N</em>-benzyl-thieno[2,3-<em>c</em>]pyridine analogs (<strong>3a–i</strong>) was synthesized, with compounds <strong>3c</strong>, <strong>3f</strong>, and <strong>3g</strong> showing improved antipromastigote activity and selectivity índices (SI). Notably, compound <strong>3f</strong> demonstrated potent amastigote activities (IC₅₀ between 0.83 and 1.13 μM), comparable to amphotericin B, but with a 250-fold higher SI and low in vivo toxicity (LD₅₀ = 2000 mg/kg in <em>Zophobas morio</em>). Physicochemical and pharmacokinetic predictions using SwissADME and Osiris indicated favorable drug-like properties and oral bioavailability for <strong>3f</strong>. Molecular docking and dynamics simulations revealed strong binding affinities to Nucleoside Diphosphate Kinase (NDK) (PDB: <span><span>5GO1</span><svg><path></path></svg></span>), Dihydroorotate Dehydrogenase (DHODH) (PDB: <span><span>4WZH</span><svg><path></path></svg></span>), and Sterol 14α-Demethylase (CYP51) (PDB: <span><span>3L4D</span><svg><path></path></svg></span>), surpassing reference ligands, with stable complexes, key catalytic site interactions, low RMSD, compact Radius of gyration, and reduced RMSF, supporting their potential as conformationally stable and specific enzyme inhibitors for leishmaniasis treatment. Altogether, these findings strongly highlight the potential of <em>N</em>-substituted thieno[2,3-<em>c</em>]pyridine as promising scaffolds for antileishmanial drug development and highlight compound <strong>3f</strong> as a lead candidate for further optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118475"},"PeriodicalIF":3.0,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.bmc.2025.118474
Xiaodi Xu , Haoran Zhu , Qingbo Shao , Baiyu Chen , Jing Lin , Yang Gao , Zhenzhou He , Wei Fu , Wei Li
Opioid analgesics remain a cornerstone of pain management, among which μ-opioid receptor (MOR) agonists dominate clinical practice due to their well-established efficacy. However, dose related adverse effects (e.g., respiratory depression, addiction potential) constrain their therapeutic utility, driving sustained efforts to develop novel MOR agonists with improved safety profiles. Building upon our previously identified lead compound FWB2, a series of 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)piperidin-4-ol derivatives was designed via structure-based drug design (SBDD), synthesized, and systematically evaluated through comprehensive in vitro and in vivo pharmacological profiling. Systematic structure-activity relationship (SAR) exploration identified (R, (3R,4S))-6c as a novel and selective MOR agonist (MOR Ki = 0.9 nM, MOR: DOR: KOR = 1: 561.1: 188.3; MOR EC50 = 89.9 nM), demonstrating potent antinociceptive activity (ED50 = 1.63 mg/kg) in the hot plate model. Molecular docking studies elucidated the binding mode of (R,(3R,4S))-6c with the MOR, identifying its molecular interactions with four critical residues W3187.35, D1473.32, H54 and W2936.48, while delineating the structural features of the ligand-receptor binding pocket.
阿片类镇痛药仍然是疼痛治疗的基石，其中μ-阿片受体（MOR）激动剂因其公认的疗效而在临床应用中占主导地位。然而，剂量相关的副作用（如呼吸抑制、成瘾性）限制了它们的治疗效用，促使人们持续努力开发具有更高安全性的新型MOR激动剂。以我们先前鉴定的先导化合物FWB2为基础，通过基于结构的药物设计（SBDD）设计了一系列3-（（二甲氨基）甲基）-4-（3-甲氧基苯基）哌啶-4-醇衍生物，进行了合成，并通过全面的体外和体内药理学分析进行了系统评估。系统构效关系（SAR）探索发现(R, (3R,4S))-6c是一种新型的选择性MOR激动剂（MOR Ki = 0.9 nM, MOR: DOR: KOR = 1:56 61.1: 188.3; MOR EC50 = 89.9 nM），在热板模型中显示出强大的抗伤感受活性（ED50 = 1.63 mg/kg）。分子对接研究阐明了(R,(3R,4S))-6c与MOR的结合模式，鉴定了其与四个关键残基W3187.35、D1473.32、H54和W2936.48的分子相互作用，同时描绘了配体-受体结合袋的结构特征。
{"title":"Discovery, SAR, and molecular basis of (R)-1-((3R,4S)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-3-(3-fluorophenyl)-2-methylpropan-1-one as a novel potent analgesic","authors":"Xiaodi Xu , Haoran Zhu , Qingbo Shao , Baiyu Chen , Jing Lin , Yang Gao , Zhenzhou He , Wei Fu , Wei Li","doi":"10.1016/j.bmc.2025.118474","DOIUrl":"10.1016/j.bmc.2025.118474","url":null,"abstract":"<div><div>Opioid analgesics remain a cornerstone of pain management, among which μ-opioid receptor (MOR) agonists dominate clinical practice due to their well-established efficacy. However, dose related adverse effects (<em>e.g.</em>, respiratory depression, addiction potential) constrain their therapeutic utility, driving sustained efforts to develop novel MOR agonists with improved safety profiles. Building upon our previously identified lead compound <strong>FWB2</strong>, a series of 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)piperidin-4-ol derivatives was designed <em>via</em> structure-based drug design (SBDD), synthesized, and systematically evaluated through comprehensive <em>in vitro</em> and <em>in vivo</em> pharmacological profiling. Systematic structure-activity relationship (SAR) exploration identified (<em>R,</em> (3<em>R,</em>4<em>S</em>))-<strong>6c</strong> as a novel and selective MOR agonist (MOR <em>K</em><sub><em>i</em></sub> = 0.9 nM, MOR: DOR: KOR = 1: 561.1: 188.3; MOR EC<sub>50</sub> = 89.9 nM), demonstrating potent antinociceptive activity (ED<sub>50</sub> = 1.63 mg/kg) in the hot plate model. Molecular docking studies elucidated the binding mode of (<em>R,</em>(3<em>R,</em>4<em>S</em>))-<strong>6c</strong> with the MOR, identifying its molecular interactions with four critical residues W318<sup>7.35</sup>, D147<sup>3.32</sup>, H54 and W293<sup>6.48</sup>, while delineating the structural features of the ligand-receptor binding pocket.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118474"},"PeriodicalIF":3.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.bmc.2025.118468
Tatiana A. Dias , David Siegel , David Ross , Christopher J. Moody
An improved route to the indolequinone pharmacophore is described based on the reaction of bromobenzoquinones with enamines. Through the implementation of small changes in the reaction conditions, the reaction conditions were much improved with quantities of copper salt, base, and acetonitrile solvent all reduced compared with the original method. The resulting indolequinone-3-carboxylates were subsequently converted into novel indolequinones as potential inhibitors of the quinone reductase enzyme NQO2. A number of potent, mechanism-based inhibitors were identified, increasing our understanding of structure-activity relationships for inhibition of this enzyme.
{"title":"Indolequinone inhibitors of NRH:quinone oxidoreductase 2. Further structure-activity relationships","authors":"Tatiana A. Dias , David Siegel , David Ross , Christopher J. Moody","doi":"10.1016/j.bmc.2025.118468","DOIUrl":"10.1016/j.bmc.2025.118468","url":null,"abstract":"<div><div>An improved route to the indolequinone pharmacophore is described based on the reaction of bromobenzoquinones with enamines. Through the implementation of small changes in the reaction conditions, the reaction conditions were much improved with quantities of copper salt, base, and acetonitrile solvent all reduced compared with the original method. The resulting indolequinone-3-carboxylates were subsequently converted into novel indolequinones as potential inhibitors of the quinone reductase enzyme NQO2. A number of potent, mechanism-based inhibitors were identified, increasing our understanding of structure-activity relationships for inhibition of this enzyme.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118468"},"PeriodicalIF":3.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bromodomain-containing protein 4 (BRD4), a key member of the BET family, is integral to epigenetic regulation through its recognition of acetylated histones and its modulation of transcriptional programs associated with cell cycle progression, DNA damage repair, and inflammatory responses. The overexpression of BRD4 has been linked to a diverse array of malignancies, including basal-like breast cancer, melanoma, and epithelial ovarian cancer, thereby establishing it as a promising therapeutic target. In the past year, significant advancements have been made in the development of novel agents targeting BRD4, particularly selective inhibitors and proteolysis-targeting chimeras (PROTACs), which demonstrate enhanced efficacy and specificity. This review provides a comprehensive summary of the functions and underlying mechanisms of BRD4 in oncogenesis. It further highlights the recent progress in the development of BRD4-directed inhibitors and degraders in the past year. Additionally, the review discusses emerging mechanisms of resistance to BRD4-targeted therapies and explores rational combination strategies to mitigate such resistance. The objective of this overview is to offer timely and insightful information that may facilitate the advancement of more effective epigenetic therapies targeting BRD4-dependent cancers.
{"title":"Targeting BRD4 in cancer therapy: From inhibitors and degraders to novel combination strategies and resistance mechanisms","authors":"Xi-Bo Wang, Rui-Jing Meng, Wen-Jin Cao, Lei Cheng, Junmin Zhang, Shi-Wu Chen","doi":"10.1016/j.bmc.2025.118473","DOIUrl":"10.1016/j.bmc.2025.118473","url":null,"abstract":"<div><div>Bromodomain-containing protein 4 (BRD4), a key member of the BET family, is integral to epigenetic regulation through its recognition of acetylated histones and its modulation of transcriptional programs associated with cell cycle progression, DNA damage repair, and inflammatory responses. The overexpression of BRD4 has been linked to a diverse array of malignancies, including basal-like breast cancer, melanoma, and epithelial ovarian cancer, thereby establishing it as a promising therapeutic target. In the past year, significant advancements have been made in the development of novel agents targeting BRD4, particularly selective inhibitors and proteolysis-targeting chimeras (PROTACs), which demonstrate enhanced efficacy and specificity. This review provides a comprehensive summary of the functions and underlying mechanisms of BRD4 in oncogenesis. It further highlights the recent progress in the development of BRD4-directed inhibitors and degraders in the past year. Additionally, the review discusses emerging mechanisms of resistance to BRD4-targeted therapies and explores rational combination strategies to mitigate such resistance. The objective of this overview is to offer timely and insightful information that may facilitate the advancement of more effective epigenetic therapies targeting BRD4-dependent cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118473"},"PeriodicalIF":3.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1016/j.bmc.2025.118471
Pedro Augusto Lemos Santana, Rafael Christian de Matos, Ana Flávia Alvarenga Bitencourt, Vinícius Gonçalves Maltarollo, Marta Marques Gontijo de Aguiar, Renes Resende Machado, Renata Barbosa de Oliveira
The endocannabinoid system plays a critical role in regulating pathophysiological processes and represents a promising target for novel therapies aimed at neurodegenerative disorders. Anandamide (AEA) mediates its therapeutic effects, particularly in pain modulation; however, its clinical potential is constrained by rapid degradation via fatty acid amide hydrolase (FAAH). The keto-oxazolopyridine derivative OL-135 is a potent FAAH inhibitor (IC50 = 4.7 nM). In this study, molecular docking simulations using three distinct protocols were performed to evaluate the binding modes of 44 arylfuran analogs of OL-135 at the FAAH enzyme binding site. These analyses identified several promising candidates, including analogs 2 and 24, which were subsequently synthesized, characterized, and tested in experimental models of pain and inflammation in mice. Carrageenan-induced pain and paw edema were used to investigate the antinociceptive and anti-inflammatory activities. Also, hot plate test was employed to evaluate the antinociceptive activity. Compound 2 significantly reduced mechanical allodynia and acute paw edema induced by carrageenan. Compounds 2 and 24 (5, 25 and 100 mg/Kg, i.p.) reduced the nociceptive response in model of nociceptive pain (hot plate). The activity of compound 2 (100 mg/Kg) in the model of nociceptive pain was attenuated by previous administration of AM251 (4 and 8 mg/Kg, i.p.). Importantly, compound 2 demonstrated no adverse effects on key biochemical parameters indicative of cardiotoxicity, hepatotoxicity, or nephrotoxicity. These findings underscore the potential of arylfuran analogs as analgesic and anti-inflammatory agents, paving the way for further development of therapeutic molecules.
{"title":"Design of arylfurans as potential FAAH inhibitors: therapeutic potential in pain management","authors":"Pedro Augusto Lemos Santana, Rafael Christian de Matos, Ana Flávia Alvarenga Bitencourt, Vinícius Gonçalves Maltarollo, Marta Marques Gontijo de Aguiar, Renes Resende Machado, Renata Barbosa de Oliveira","doi":"10.1016/j.bmc.2025.118471","DOIUrl":"10.1016/j.bmc.2025.118471","url":null,"abstract":"<div><div>The endocannabinoid system plays a critical role in regulating pathophysiological processes and represents a promising target for novel therapies aimed at neurodegenerative disorders. Anandamide (AEA) mediates its therapeutic effects, particularly in pain modulation; however, its clinical potential is constrained by rapid degradation via fatty acid amide hydrolase (FAAH). The keto-oxazolopyridine derivative OL-135 is a potent FAAH inhibitor (IC<sub>50</sub> = 4.7 nM). In this study, molecular docking simulations using three distinct protocols were performed to evaluate the binding modes of 44 arylfuran analogs of OL-135 at the FAAH enzyme binding site. These analyses identified several promising candidates, including analogs <strong>2</strong> and <strong>24</strong>, which were subsequently synthesized, characterized, and tested in experimental models of pain and inflammation in mice. Carrageenan-induced pain and paw edema were used to investigate the antinociceptive and anti-inflammatory activities. Also, hot plate test was employed to evaluate the antinociceptive activity. Compound <strong>2</strong> significantly reduced mechanical allodynia and acute paw edema induced by carrageenan. Compounds <strong>2</strong> and <strong>24</strong> (5, 25 and 100 mg/Kg, i.p.) reduced the nociceptive response in model of nociceptive pain (hot plate). The activity of compound 2 (100 mg/Kg) in the model of nociceptive pain was attenuated by previous administration of AM251 (4 and 8 mg/Kg, i.p.). Importantly, compound <strong>2</strong> demonstrated no adverse effects on key biochemical parameters indicative of cardiotoxicity, hepatotoxicity, or nephrotoxicity. These findings underscore the potential of arylfuran analogs as analgesic and anti-inflammatory agents, paving the way for further development of therapeutic molecules.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118471"},"PeriodicalIF":3.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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