Pub Date : 2025-10-30DOI: 10.1016/j.bmcl.2025.130457
Hannah L. Bolt , Marcel Kaiser , Yu Luo , Fionnuala T. Lundy , Libbi Moon , Ronald N. Zuckermann , Paul W. Denny , Steven L. Cobb
Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid 29 [NamyNspeNspe)(NhArgNspeNspe)]2 had an IC50 of 0.05 μM against Plasmodium falciparum and a SI > 100.
{"title":"Bioactive peptoids against vector-borne parasitic diseases","authors":"Hannah L. Bolt , Marcel Kaiser , Yu Luo , Fionnuala T. Lundy , Libbi Moon , Ronald N. Zuckermann , Paul W. Denny , Steven L. Cobb","doi":"10.1016/j.bmcl.2025.130457","DOIUrl":"10.1016/j.bmcl.2025.130457","url":null,"abstract":"<div><div>Protozoan parasites represent a severe threat to global human health as they are responsible for infection in Malaria, and a range of Neglected Tropical Diseases (NTDs) including Chagas disease, leishmaniasis and African sleeping sickness. Often treatments for protozan parasites are limited in their efficacy and drug resistance is an emerging problem. The current efforts to develop new treatments for the aforementioned diseases have been met with limited success and as such novel compound classes for development are being actively sought. Peptoids are peptidomimetics that have showed promise as antimicrobial agents but their application in the field of vector-borne parasitic diseases is highly underdeveloped. Herein, a library of over 50 peptoids containing a wide variety of chemical functionalities has been prepared and biologically evaluated against a range of protozoan parasitic targets. Selected members of the peptoid library were found to have potent anti-parasitic activity and good selectivity indices (SI). For example, peptoid <strong>29</strong> [<em>N</em>amy<em>N</em>spe<em>N</em>spe)(<em>N</em>hArg<em>N</em>spe<em>N</em>spe)]<sub>2</sub> had an IC<sub>50</sub> of 0.05 μM against <em>Plasmodium falciparum</em> and a SI > 100.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130457"},"PeriodicalIF":2.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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.bmcl.2025.130459
Nicole Wandrey , Jake Boley , Dirce Gómez-Galicia , Mackinzi Hill , Mason Bach , Sidney Gawrych , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas
Arylalkylamine N-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound 5g (bearing a CH3CO2CH2- substituent) resulting in an IC₅₀ of 1.1 μM—representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.
芳基烷基胺n -乙酰转移酶（AANAT）是褪黑激素生物合成的关键酶，也是昼夜节律的调节剂，与季节性情感障碍（SAD）等情绪障碍有潜在关联。我们报道了一系列以吲哚啉酮为基础的AANAT抑制剂，作为先前报道的罗丹宁支架更稳定的替代品。在对接研究和先前的结构活性数据的指导下，我们修改了分子的四个区域以提高效力。吲哚酮环5位的取代导致活性显着增加，化合物5g（含有CH3CO2CH2-取代基）导致IC₅0为1.1 μ m -比母体化合物提高了19倍。还进行了关于乙酰辅酶a和血清素的动力学机制研究，以探索抑制剂的结合。这些发现为开发更有效的AANAT抑制剂作为研究褪黑激素功能的化学探针奠定了一个有希望的起点。
{"title":"Hydantion indolinones as AANAT inhibitors","authors":"Nicole Wandrey , Jake Boley , Dirce Gómez-Galicia , Mackinzi Hill , Mason Bach , Sidney Gawrych , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas","doi":"10.1016/j.bmcl.2025.130459","DOIUrl":"10.1016/j.bmcl.2025.130459","url":null,"abstract":"<div><div>Arylalkylamine <em>N</em>-acetyltransferase (AANAT) is a key enzyme in melatonin biosynthesis and a regulator of circadian rhythm, with potential relevance to mood disorders such as seasonal affective disorder (SAD). We report a series of hydantoin indolinone-based AANAT inhibitors, developed as more stable alternatives to a previously reported rhodanine scaffold. Guided by docking studies and prior structure-activity data, we modified four regions of the molecule to improve potency. Substitution at the 5-position of the indolinone ring led to marked increases in activity, with compound <strong>5g</strong> (bearing a CH<sub>3</sub>CO<sub>2</sub>CH<sub>2</sub>- substituent) resulting in an IC₅₀ of 1.1 μM—representing a 19-fold improvement over the parent compound. Kinetic mechanism studies were also conducted with respect to acetyl-CoA and serotonin to explore inhibitor binding. These findings establish a promising starting point for the development of more potent AANAT inhibitors as chemical probes for studying melatonin's function.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130459"},"PeriodicalIF":2.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumors remain a leading cause of mortality worldwide, and existing clinical treatments face challenges such as high toxicity, poor efficacy, and multidrug resistance. Natural products have emerged as promising sources for developing anticancer drugs due to their high efficacy and low toxicity. Curcumin, a yellow polyphenolic compound with diverse biological activities (anti-tumor, antiviral, antibacterial, and anti-HIV), is particularly notable for its minimal toxic side effects. However, its clinical application is hindered by low oral bioavailability and instability. To address these limitations, this study designed and synthesized nine novel monocarbonyl curcumin analogs by removing the unstable β-diketone group and introducing ferrocene-based structures with piperidone derivatives. Using ferrocene as a starting material, these asymmetric compounds were synthesized through Vilsmeier and Claisen-Schmidt reactions, followed by structural confirmation using 1H NMR, MS, and 13C NMR. Antitumor activity was evaluated against MCF-7, PC-3, and A549 tumor cells using the CCK-8 method, with curcumin as a control. Notably, several analogs exhibited dramatically enhanced potency. Compound 1a was identified as the most promising derivative, showing 4.7-, 7.4-, and 2.0-fold higher potency than curcumin against A549, PC-3, and MCF-7 cells, respectively (IC₅₀ = 6.11, 5.21, and 10.37 μM vs. 28.92, 38.53, and 20.82 μM for curcumin). These findings provide a foundation for further development of ferrocene-modified curcumin analogs as potential anticancer agents.
{"title":"Ferrocene-modified cyclic asymmetric curcumin analogs: Synthesis and enhanced antitumor activity","authors":"Haotian Xie , Wenjie Xiao , Ruichen Xie , Lifang Xu , Shuhui Ren , Hanfeng Cui","doi":"10.1016/j.bmcl.2025.130446","DOIUrl":"10.1016/j.bmcl.2025.130446","url":null,"abstract":"<div><div>Tumors remain a leading cause of mortality worldwide, and existing clinical treatments face challenges such as high toxicity, poor efficacy, and multidrug resistance. Natural products have emerged as promising sources for developing anticancer drugs due to their high efficacy and low toxicity. Curcumin, a yellow polyphenolic compound with diverse biological activities (anti-tumor, antiviral, antibacterial, and anti-HIV), is particularly notable for its minimal toxic side effects. However, its clinical application is hindered by low oral bioavailability and instability. To address these limitations, this study designed and synthesized nine novel monocarbonyl curcumin analogs by removing the unstable β-diketone group and introducing ferrocene-based structures with piperidone derivatives. Using ferrocene as a starting material, these asymmetric compounds were synthesized through Vilsmeier and Claisen-Schmidt reactions, followed by structural confirmation using <sup>1</sup><em>H</em> NMR, MS, and <sup>13</sup><em>C</em> NMR. Antitumor activity was evaluated against MCF-7, PC-3, and A549 tumor cells using the CCK-8 method, with curcumin as a control. Notably, several analogs exhibited dramatically enhanced potency. Compound <strong>1a</strong> was identified as the most promising derivative, showing 4.7-, 7.4-, and 2.0-fold higher potency than curcumin against A549, PC-3, and MCF-7 cells, respectively (IC₅₀ = 6.11, 5.21, and 10.37 μM vs. 28.92, 38.53, and 20.82 μM for curcumin). These findings provide a foundation for further development of ferrocene-modified curcumin analogs as potential anticancer agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130446"},"PeriodicalIF":2.2,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145413910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-22DOI: 10.1016/j.bmcl.2025.130442
Yong Wang , Yingchuan Que , Yi Gu , Jia Xia , Yi Dong , Lumin Tang , Shan Mou , Gang Chen
Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (11a) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and 11a effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative 11a emerging as a particularly promising candidate for further development.
{"title":"Late-stage functionalization of Cycloastragenol and anti-inflammatory study","authors":"Yong Wang , Yingchuan Que , Yi Gu , Jia Xia , Yi Dong , Lumin Tang , Shan Mou , Gang Chen","doi":"10.1016/j.bmcl.2025.130442","DOIUrl":"10.1016/j.bmcl.2025.130442","url":null,"abstract":"<div><div>Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (<strong>11a</strong>) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and <strong>11a</strong> effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative <strong>11a</strong> emerging as a particularly promising candidate for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130442"},"PeriodicalIF":2.2,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.bmcl.2025.130440
Xu Hu , Xiaoni Yu , Yutian Zhang , Biao Zhou , Chao Li , Dahong Li , Shengge Li , Xianzhang Huang
Natural β-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of β-carboline, a range of β-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (12a-c, 13a-d, 14a-d, and 15a-d) were evaluated for in vitro cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid 12c exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC50 value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC50 > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that 12c induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that 12c exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, 12c may represent a promising anti-leukemia agent and warrants further investigation.
{"title":"Enhancement of anticancer potential of novel β-carboline derivatives by ACS81 hybridization","authors":"Xu Hu , Xiaoni Yu , Yutian Zhang , Biao Zhou , Chao Li , Dahong Li , Shengge Li , Xianzhang Huang","doi":"10.1016/j.bmcl.2025.130440","DOIUrl":"10.1016/j.bmcl.2025.130440","url":null,"abstract":"<div><div>Natural <em>β</em>-carboline alkaloids are currently under extensive scrutiny for their antitumor properties. To improve the antitumor efficacy of <em>β</em>-carboline, a range of <em>β</em>-carboline-ACS81 hybrids were created through molecular hybridization with diallyl disulfide derivatives, and preliminary structure-activity relationships (SAR) were established. Furthermore, the newly synthesized hybrids (<strong>12a-c</strong>, <strong>13a-d</strong>, <strong>14a-d</strong>, and <strong>15a-d</strong>) were evaluated for <em>in vitro</em> cytotoxicity against a panel of six human cancer cell lines (HL-60, U937, HepG2, HCT-116, A375, and A549), as well as one normal human hepatic cell line (L-02). Among them, hybrid <strong>12c</strong> exhibited the strongest inhibitory activity against the HL-60 cell line, with an IC<sub>50</sub> value of 1.52 μM, surpassing the efficacy of the positive control drug 5-FU. Moreover, this compound displayed minimal cytotoxicity against L-02 cells (IC<sub>50</sub> > 30 μM), indicating a favorable selectivity profile between tumor cells and normal cells. Comprehensive investigations revealed that <strong>12c</strong> induced apoptosis by arresting the cell cycle at the G2/M phase. This effect was achieved by inducing alterations in nuclear morphology and the collapse of mitochondrial membrane potential. These findings suggested that <strong>12c</strong> exerted an antiproliferative impact by triggering apoptosis through the mitochondrial pathway. Given these observations, <strong>12c</strong> may represent a promising anti-leukemia agent and warrants further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130440"},"PeriodicalIF":2.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.bmcl.2025.130443
En-Jie Zhu , Xing-Sheng Bu , Ying Yue , Yong-Sheng Hou , Jia-Rong Liu , Tharcisse Gatera , Shu-Yang Ni , Tian Chai , Xing-Rong Wang , Jun-Li Yang
Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.
{"title":"Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents","authors":"En-Jie Zhu , Xing-Sheng Bu , Ying Yue , Yong-Sheng Hou , Jia-Rong Liu , Tharcisse Gatera , Shu-Yang Ni , Tian Chai , Xing-Rong Wang , Jun-Li Yang","doi":"10.1016/j.bmcl.2025.130443","DOIUrl":"10.1016/j.bmcl.2025.130443","url":null,"abstract":"<div><div>Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative <strong>W-1</strong>. Among them, <strong>Z12</strong> showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. <strong>Z12</strong> promoted HIF-1α degradation <em>via</em> the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, <strong>Z12</strong> inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130443"},"PeriodicalIF":2.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.bmcl.2025.130447
Oluseye K. Onajole , Shichun Lun , Dakoju Ravi Kishore , Anđela Savić , Alexis Morales , Alfredo Guzman , Ethan Schmidt , Adela Lazzara , Gianna Fajardo , Daniel P. Jamieson , A. Jean-Luc Ayitou , William R. Bishai
Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are limited safe therapeutics available to combat multidrug- and extensively drug-resistant (MDR and XDR, respectively) strains of TB, hence the race to find highly effective antitubercular drug candidates with little to no side effects. Herein, we report on the design, synthesis, and biological evaluation of 33 novel heterobicyclic (imidazothiazole- and imidazopyrimidine-containing) carboxamide derivatives for their antitubercular properties. These compounds were designed based on reported anti-TB properties of indole-2-carboxamides, imidazo[1,2-a]pyridine-3-carboxamides, and imidazo[2,1-b]pyrimidine-5-carboxamides derivatives. This effort led to the discovery of compounds 21 (imidazothiazole-based) and 37 (imidazopyrimidine-based), which showed excellent anti-TB activity against susceptible, MDR, and XDR-TB strains (MIC: 0.2–6.36 μM). Compound 21 also displayed excellent drug-like properties based on its pharmacokinetic profiles and is void of cytotoxicity to Vero cells at the highest tested concentration. Importantly, compounds 21 and 37 were found to be inactive against selected non-TB forming mycobacteria (MIC: >40 μM) and bacteria (both gram-negative and gram-positive microorganisms), indicating their selectivity for Mycobacterium tuberculosis.
{"title":"Exploration of imidazothiazole and imidazopyrimidine carboxamides for enhanced antitubercular activity","authors":"Oluseye K. Onajole , Shichun Lun , Dakoju Ravi Kishore , Anđela Savić , Alexis Morales , Alfredo Guzman , Ethan Schmidt , Adela Lazzara , Gianna Fajardo , Daniel P. Jamieson , A. Jean-Luc Ayitou , William R. Bishai","doi":"10.1016/j.bmcl.2025.130447","DOIUrl":"10.1016/j.bmcl.2025.130447","url":null,"abstract":"<div><div>Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are limited safe therapeutics available to combat multidrug- and extensively drug-resistant (MDR and XDR, respectively) strains of TB, hence the race to find highly effective antitubercular drug candidates with little to no side effects. Herein, we report on the design, synthesis, and biological evaluation of 33 novel heterobicyclic (imidazothiazole- and imidazopyrimidine-containing) carboxamide derivatives for their antitubercular properties. These compounds were designed based on reported anti-TB properties of indole-2-carboxamides, imidazo[1,2-<em>a</em>]pyridine-3-carboxamides, and imidazo[2,1-<em>b</em>]pyrimidine-5-carboxamides derivatives. This effort led to the discovery of compounds <strong>21</strong> (imidazothiazole-based) and <strong>37</strong> (imidazopyrimidine-based), which showed excellent anti-TB activity against susceptible, MDR, and XDR-TB strains (MIC: 0.2–6.36 μM). Compound <strong>21</strong> also displayed excellent drug-like properties based on its pharmacokinetic profiles and is void of cytotoxicity to Vero cells at the highest tested concentration. Importantly, compounds <strong>21</strong> and <strong>37</strong> were found to be inactive against selected non-TB forming mycobacteria (MIC: >40 μM) and bacteria (both gram-negative and gram-positive microorganisms), indicating their selectivity for <em>Mycobacterium tuberculosis</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130447"},"PeriodicalIF":2.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.bmcl.2025.130441
Johanna Y.D. Asante , Elise L. Bezold , William M. Wuest , Kevin P.C. Minbiole
Due to the relentless advance of bacterial resistance mechanisms, there exists an urgent need to develop novel surface disinfectants that eradicate a wide range of pathogenic bacteria. Our efforts in this arena have focused on optimization of potency, resistance-to-resistance, and safety. Herein, we report the efficient and modular construction of a series of triscationic quaternary ammonium compounds with a bolaamphiphilic architecture, based on a versatile phloroglucinol core where the cationic residues are either quaternized nitrogen atoms or imidazolium residues. A broad subset of the 28 prepared structures boast single-digit micromolar activity against a panel of eight bacteria that represent Gram-positive, Gram-negative, and resistant strains. Importantly, we have identified structure-activity relationships that highlight a set of four compounds (PHL-6,8, PHL-8,6, PHL-4-imid-8, and PHL-6-imid-6) that have MIC values generally ≤2 μM, as well as therapeutic indices (using red blood cell lysis as a proxy) of 32–250. Interestingly, a series of compounds with a single additional carbon per side chain shows marginally better potency (average MIC = 1 μM) but a significant jump in eukaryotic toxicity, dropping TI levels significantly. These observations reinforce the importance of amphiphilic balance in the development of disinfectant structures.
{"title":"Triscationic bolaamphiphilic QACs – optimizing antibacterial therapeutic indices","authors":"Johanna Y.D. Asante , Elise L. Bezold , William M. Wuest , Kevin P.C. Minbiole","doi":"10.1016/j.bmcl.2025.130441","DOIUrl":"10.1016/j.bmcl.2025.130441","url":null,"abstract":"<div><div>Due to the relentless advance of bacterial resistance mechanisms, there exists an urgent need to develop novel surface disinfectants that eradicate a wide range of pathogenic bacteria. Our efforts in this arena have focused on optimization of potency, resistance-to-resistance, and safety. Herein, we report the efficient and modular construction of a series of triscationic quaternary ammonium compounds with a bolaamphiphilic architecture, based on a versatile phloroglucinol core where the cationic residues are either quaternized nitrogen atoms or imidazolium residues. A broad subset of the 28 prepared structures boast single-digit micromolar activity against a panel of eight bacteria that represent Gram-positive, Gram-negative, and resistant strains. Importantly, we have identified structure-activity relationships that highlight a set of four compounds (<strong>PHL-6,8</strong>, <strong>PHL-8,6</strong>, <strong>PHL-4-imid-8</strong>, and <strong>PHL-6-imid-6</strong>) that have MIC values generally ≤2 μM, as well as therapeutic indices (using red blood cell lysis as a proxy) of 32–250. Interestingly, a series of compounds with a single additional carbon per side chain shows marginally better potency (average MIC = 1 μM) but a significant jump in eukaryotic toxicity, dropping TI levels significantly. These observations reinforce the importance of amphiphilic balance in the development of disinfectant structures.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130441"},"PeriodicalIF":2.2,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-19DOI: 10.1016/j.bmcl.2025.130439
Danqing Li , Yumiao Zhen , Ran Tang , Boying Wang , Haijing Zhong , Xiaojian Jiang , Ying-Yeung Yeung
The cytotoxicity of α-exo-methylene-lactones has been extensively studied. However, further study of the α-exo-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility. In the present work, a series of α-exo-methylene-selenolactone derivatives bearing amine substituent, selenium functionality and quaternary carbon center were synthesized and evaluated for their anticancer activities. The most potent compound, 2d, was about 9-fold more selective for cancer cells than normal cells. Moreover, 2d significantly inhibited tumor growth in mouse xenograft model and had no observable toxic effect.
{"title":"Synthesis and antitumor activities of quaternary carbon-containing selenolactones","authors":"Danqing Li , Yumiao Zhen , Ran Tang , Boying Wang , Haijing Zhong , Xiaojian Jiang , Ying-Yeung Yeung","doi":"10.1016/j.bmcl.2025.130439","DOIUrl":"10.1016/j.bmcl.2025.130439","url":null,"abstract":"<div><div>The cytotoxicity of α-<em>exo</em>-methylene-lactones has been extensively studied. However, further study of the α-<em>exo</em>-methylene-lactones for anticancer application was hampered primarily by its poor selectivity and solubility. In the present work, a series of α-<em>exo</em>-methylene-selenolactone derivatives bearing amine substituent, selenium functionality and quaternary carbon center were synthesized and evaluated for their anticancer activities. The most potent compound, <strong>2d</strong>, was about 9-fold more selective for cancer cells than normal cells. Moreover, <strong>2d</strong> significantly inhibited tumor growth in mouse xenograft model and had no observable toxic effect.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130439"},"PeriodicalIF":2.2,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study describes the development of novel dibenzyl ether derivatives that selectively inhibit intestinal CYP3A4 and are expected to function as pharmacokinetic boosters. Based on previously reported phenylazole derivatives, new compounds were synthesized by systematically modifying the azole moiety, linker structure, and ester functionality to explore structure–activity relationships. The selected dibenzyl ether derivatives exhibited potent CYP3A4 inhibitory activity and remained stable in the presence of intestinal S9 fractions, whereas they were rapidly metabolized in liver S9 fractions to form less active metabolites. The ability to undergo rapid hepatic metabolism is considered advantageous for reducing the risk of drug–drug interactions. These findings suggest that the dibenzyl ether derivatives represent a promising lead for the development of intestine-selective pharmacokinetic booster candidates.
{"title":"Discovery of a novel pharmacokinetic booster: A small intestine-selective CYP3A4 inhibitor with dibenzyl ether structure","authors":"Shoki Hoshikawa, Koki Kimura, Chisaki Hanada, Yukiko Karuo, Atsushi Tarui, Kazuyuki Sato, Masaaki Omote, Makoto Kataoka, Kentaro Kawai","doi":"10.1016/j.bmcl.2025.130445","DOIUrl":"10.1016/j.bmcl.2025.130445","url":null,"abstract":"<div><div>This study describes the development of novel dibenzyl ether derivatives that selectively inhibit intestinal CYP3A4 and are expected to function as pharmacokinetic boosters. Based on previously reported phenylazole derivatives, new compounds were synthesized by systematically modifying the azole moiety, linker structure, and ester functionality to explore structure–activity relationships. The selected dibenzyl ether derivatives exhibited potent CYP3A4 inhibitory activity and remained stable in the presence of intestinal S9 fractions, whereas they were rapidly metabolized in liver S9 fractions to form less active metabolites. The ability to undergo rapid hepatic metabolism is considered advantageous for reducing the risk of drug–drug interactions. These findings suggest that the dibenzyl ether derivatives represent a promising lead for the development of intestine-selective pharmacokinetic booster candidates.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130445"},"PeriodicalIF":2.2,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145342479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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