Synthesis, spectroscopic, theoretical and computational investigations of novel indole fused tris-heterocyclic compounds: as high portentous antimicrobial agents

作者: Joshi, Shrinivas Dattatraya ; Anjanayya, Govinda ; Adole, Vishnu Ashok ; Mathada, Basavarajaiah Suliphuldevarada ; Bashetti, Nivedita Rajashekhar ; Hiremath, Murigendra Basayya ; Mangalawede, Shailendra Shivand ; Gani, Ramesh Sabu ; Bonagiri, Rajesh

In the human microbiome, bacteria seem to be far more prevalent than viruses, fungi, and protozoa, and bacterial illnesses are also common.As a result, microbial resistance poses serious problems for public health.Since growing bacterial and fungal resistance to antimicrobial medicines poses a serious danger to global public health, the development of novel antimicrobial medications is both urgently needed and crucial.Through spectroscopic examination, new indole fused tris heterocyclic compounds including triazole, thiazole,pyrrole and oxadiazole were clarified.We evaluated the compounds′ in vitro antibacterial and antifungal efficacy using the agar diffusion technique.After checking the pharmacokinetic features and ADME in silico predictions, the made compounds were put through mol. docking studies and DFT calculationsThe compounds such as 10 a,11,13,14,and 17 displayed a significant antimicrobial activity against selected microbial pathogens.The docking study revealed that all the compounds have showed very good docking score against Escherichia coli.and compound 10b and 14 showed reasonable binding modes in the active site of the enzyme.In silico predictions of ADME and pharmacokinetic parameters indicated that few compounds appear to possess high pharmacol. activity, they demonstarte good absorption, permiability and oral bioavailability.The antibacterial and antifungal activity of indole fused tris heterocyclic compounds, including 10a, 13, 14, and 17, demonstrated significant antimicrobial efficacy.Docking studies, ADME, and pharmacokinetic parameters further support the results.The results indicate that compounds 10a, 13, 14, and 17 represent a promising avenue for the development of new antimicrobial drugs.

2025-05-26·ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Brønsted Acid‐Catalyzed Atroposelective Coupling of Carboxylic Acids with Amines and Alcohols via Ynamide Mediation

Article

作者: Jiang, Jia‐Tian ; Yang, Ye‐Nan ; Chen, Hua‐Hong ; Ye, Long‐Wu ; Zhou, Bo

Abstract:

Carboxylic acids are readily available chemicals with broad applications in chemistry‐related areas, and their coupling with amines and alcohols is a fundamental transformation in organic synthesis. However, the catalytic enantioselective coupling of carboxylic acids remains elusive, especially for the atroposelective reaction. Here we report a chiral Brønsted acid (CBA)‐catalyzed atroposelective coupling of carboxylic acids with amines and alcohols using ynamides as coupling reagents. The novel enantiocontrol involving CBA‐catalyzed ester addition enables the straightforward construction of axially chiral amides and planar‐chiral esters with high enantioselectivities through atroposelective intermolecular amidation and intramolecular macrolactonization. Diverse medicinally relevant carboxylic acids can undergo direct late‐stage modification by this method. Importantly, this reaction represents the first atroposelective coupling of carboxylic acids with amines, as well as the first chemocatalytic atroposelective coupling of carboxylic acids with alcohols. The resulting atropisomeric skeletons can be readily derivatized to chiral ligands and catalysts for asymmetric catalysis.

2025-04-21·ACS Sustainable Chemistry & Engineering

A New Green Oxyma-Sulfonate Coupling Reagent for Sustainable Organic Transformations

作者: Mandal, Bhubaneswar ; Roy, Sayanta

In this dynamic era, waste accumulation due to population growth and industrialization threatens ecosystems and human health.Scientists now prioritize recycling and sustainable chem. practices to mitigate these challenges.Syntheses of amide and ester moieties, crucial in medicinal chem., rely on coupling reagents in academia and in industries.However, classical protocols fall short of Green Chem. standards using excess reagents and toxic and expensive solvents.Moreover, widely used hazardous coupling reagents and solvents elevate environmental and human health risks.In our study, we focus on green amide, ester, and peptide synthesis, achieving racemization-free reactions using Et (E)-2-((((5-chlorothiophen-2-yl)sulfonyl)oxy)imino)-2-cyanoacetate, a novel coupling reagent.We have developed a rapid, cost-effective, environmentally friendly synthetic protocol for this coupling reagent and explored sustainable solution-phase and solid-phase peptide synthesis.Notably, we replaced the hazardous N,N-dimethylformamide with acetone in solution-phase synthesis and an EtOAc/DMSO mixture in solid-phase peptide synthesis, significantly enhancing overall sustainability.Furthermore, our efforts to recover and reuse byproducts after chem. transformations, reconstructing the same coupling reagent from them, and reusing it in the same pool have been successful.By reclaiming and recycling both solvents and coupling reagents, we actively reduced chem. waste and advanced toward greener, waste-free chem. synthesis.

项与阿西美辛相关的新闻（医药）

2024-03-05

·精准药物

含吲哚药物结构与靶点，药理与SAR 研究归纳

吲哚是一种芳香杂环分子，具有一个苯环和一个含氮吡咯环组成的双环结构。吲哚中的氮原子提供一对孤对电子，形成共轭体系，从而稳定了吲哚结构。这对孤电子使吲哚化合物呈现弱碱性(pKa=16.2和pK,=17.6)。由于吡咯环的电子密度相对较高以及氮原子的共轭效应，吲哚可以在其吡咯环的3位发生亲电取代反应(图la)。图 1 (a) 全球有超过70种含有吲哚的合成药物在市场上销售，并被证明具有良好的医疗效果(图1b)。用于治疗的疾病包括糖尿病、癌症、白血病、丙型肝炎、心理障碍和其他临床问题。自2015年起，美国(FDA)专门批准了14种含吲哚药物，其中3种是在2021年批准的(图2)。二氢麦角胺(DHE,1)的化学结构中含有吲哚支架，对头颅血管平滑肌中的5-HT1b受体具有激动活性，治疗偏头痛。昂丹司琼(2)是一种血清素5-HT3受体拮抗剂，用于预防癌症治疗期间和手术后的恶心和呕吐(图3a)。图 3 (a) 双氢麦角胺（1）和昂丹司琼（2）的结构。(b) 双氢麦角胺(1)与其靶点（左）和昂丹司琼(2)与其靶点（右）的关键靶点相互作用。替加色罗(3)在临床相关水平上被认为是5-HT(4)受体的激动剂和5-HT(2B)受体的拮抗剂，其作用之一是使受损的胃肠道运动恢复正常。多拉司琼(4)用于中度致吐的癌症化疗以及术后恶心和呕吐的治疗(图5)。它是一种高效、选择性的血清素5-HT3受体拮抗剂。 Tropisetron（5）可抑制5HT3受体上血清素的活性，从而抑制放疗和化疗引起的呕吐。 Vilazodone(6)是5HT-1A受体的部分激动剂，专门抑制中枢神经系统对血清素的再摄取。在治疗偏头痛急性发作方面，三苯氧胺药物(5-羟色胺受体激动剂)比其他药物更有效、更耐受。这类药物具有起效快、用药时间长、不良反应少等优点。Sumatriptan(7),zolmitriptan(8),naratriptan(9), rizatriptan(10), almotriptan (11), frovatriptan (12), eletriptan (13), 和 oxitriptan (14) 是国外已商业化的曲坦类药物的代表。(图7)。环氧化酶(COX)被称为前列腺素G/H合成酶，而吲哚美辛是一种非特异性的可逆性环氧化酶抑制剂。吲哚美辛(18)属于吲哚-3-乙酸类，其官能团包括对氯苯甲酰基、甲基和甲氧基。它是一种非甾体抗炎药(NSAID), 具有消炎、镇痛和解热的特点(图11a)。 Acemetacin(19)是另一种强效非甾体抗炎药物，由吲哚-3-乙酸衍生而来(图12)。它主要通过酯分解代谢为吲哚美辛。 Etodolac(20)是一种非甾体抗炎药，具有消炎、镇痛和解热作用(图13a)。以前被认为是一种非选择性COX抑制剂，但现在被认为对COX-2的选择性是COX-1的5-50倍。 Carprofen(21)是兽医用作缓解老年犬关节炎症状的辅助疗法的一种非甾体抗炎药，人们认为卡洛芬(21)的作用机制是抑制环氧化酶的活性。帕金森病的药物 Cabergoline(22)是一种长效多巴胺受体激动剂，与D2受体有很强的亲和力，用于治疗高催乳素血症和帕金森综合症(图14a)。 Lisuride(23)可能是某些血清素受体的激动剂,也可能是多巴胺D1受体的拮抗剂。可降低催乳素水平，适量服用可阻止偏头痛，从药理上讲，(23)是还是一种帕金森氏症药物。治疗子宫脱垂的药物甲基麦角新碱(26)是一种麦角生物碱，临床上用于预防和治疗产后和流产后出血(图17)。这种药物与多巴胺D1受体结合，作为一种拮抗剂发挥作用，可增强平滑肌的张力、节奏和节律性收缩的幅度。治疗精神疾病的药物 sertindole（27）是一种抗精神分裂症药物，也是一种苯基吲哚衍生物。临床试验证实，(27)对低水平的多巴胺D2占位具有疗效。治疗神经系统疾病的药物吲哚洛尔(28)是一种非选择性β肾上腺素受体拮抗剂，用于治疗心房颤动、水肿、高血压和室性心动过速。卡维地洛(29)通过阻断β肾上腺素受体防止运动引起的心动过速，它对α-1肾上腺素能受体的作用可使血管平滑肌放松，从而降低外周血管阻力和血压。尼麦角林(30)是一种半合成麦角衍生物，可用于治疗认知功能障碍。这种药剂作为一种选择性α-1A肾上腺素能受体抑制剂用于临床(图20)。治疗生殖系统疾病的药物麦角新碱(32)是一种麦角生物碱，可用于控制妇女的产后和流产后出血。结构与活性关系明确的药物 Tezacaftor(41)属于用于治疗囊性纤维化(CFTR)增效剂。美国食品及药物管理局批准该药与ivacaftor联合用于治疗囊性纤维化(图28a)。该药物可在2至4小时内达到血浆浓度峰值。 2015年2月23日，FDA批准口服去乙酰化酶(DAC)抑制剂Panobinostat(42)用于治疗多发性骨髓瘤(图29a)。(42)在体外与人体血浆蛋白的结合率约为90%,这与其浓度无关。其吲哚环可以通过与Asn645的氢键相互作用为SAR创造一个稳定的框架(图29b)。结构与活性关系不完全明确的药物 Metergoline(52)是一种麦角衍生物，用于治疗女性高催乳素闭经症(图39)。通过靶向钠通道而非5HT受体来抑制钠通道的活性，从而导致泌乳素分泌减少。 Lurbinectedin(53)是一种抗癌天然产物。该药物在化疗中用于治疗转移性小细胞肺癌。Lurbinectedin(53)在临床试验中的治疗反应率和持续时间在2020年获得了加速批准。总体而言，在FDA批准的药物中，含有吲哚环的药物数量在不断增加。在药物分子中引入吲哚砌块也已成为药物化学和药物设计中的一种常见策略。现有的含吲哚药物因其特殊的结构，在抗癌、抗炎和抗病毒等方面具有显著的临床价值。参考文献：DOI: 10.1039/d3md00677h 内容来源于网络，如有侵权，请联系删除。

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100 项与阿西美辛相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01582	阿西美辛	M01AB11	DB13783

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
滑囊炎	中国	佛山市华普生药业有限公司	1996-01-01
疼痛	中国	佛山市华普生药业有限公司	1996-01-01
肌腱病	中国	佛山市华普生药业有限公司	1996-01-01
骨关节炎	日本	Kowa Co., Ltd.	1992-07-10
肩周炎	日本	Kowa Co., Ltd.	1992-07-10
腰痛	日本	Kowa Co., Ltd.	1992-03-16
肌肉骨骼系统疾病	日本	Kowa Co., Ltd.	1992-03-16
术后疼痛	日本	Kowa Co., Ltd.	1992-03-16
呼吸道感染	日本	Kowa Co., Ltd.	1992-03-16
创伤和损伤	日本	Kowa Co., Ltd.	1992-03-16
强直性脊柱炎	德国	Meda Pharma GmbH	1980-01-01
痛风	德国	Meda Pharma GmbH	1980-01-01
关节疾病	德国	Meda Pharma GmbH	1980-01-01
类风湿关节炎	德国	Meda Pharma GmbH	1980-01-01
血栓性静脉炎	德国	Meda Pharma GmbH	1980-01-01