Ceftazidime

Researchers have made a significant breakthrough in the field of asymmetric synthesis of beta-lactams, which are prominent in bioactive compounds. Their innovative approach employs nickel and hydrocarbon sources that are abundant on Earth to access value-added beta-lactam products. The employment of nickel-hydride catalysis and alkenyl dioxazolone derivatives gives rise to the selective formation of four-membered lactam products. Led by Director CHANG Sukbok, scientists from the Center for Catalytic Hydrocarbon Functionalizations within the Institute for Basic Science (IBS) have made a significant advancement in the synthesis of β-lactam scaffolds, which are structural components frequently found in essential antibiotics such as penicillins and carbapenems. This breakthrough overcomes challenges in β-lactam synthesis to promise streamlined pathways for drug development. The core chemical structure that makes up penicillins is a four-membered cyclic amide scaffold called chiral β-lactam,which is also frequently found in other types of major antibiotics like carbapenems and cephalosporins. The high-value potential of chiral β-lactam has been recognized in modern science given such relevance to the pharmaceutical products, which consequently evoked much efforts to synthesize them using readily available raw chemicals. Back in 2019, the IBS group unveiled a catalytic reaction that allowed access to chiral γ-lactams, five-membered amide structures that differ in the ring size from β-lactams. They managed to achieve high enantioselectivity by utilizing chiral iridium catalysts, however, the same approach could not be applied to the synthesis of the four-membered variant, β-lactam. One major obstacle in accessing β-lactams was, in fact, the outcompeting formation of γ-lactams. Overcoming this critical regioselectivity issue, while achieving high enantioselectivity at the same time, remains highly challenging for the synthesis of β-lactams. In addition, the use of costly rare earth metals can pose limitations in many aspects. To address these challenges, the IBS research team pioneered a novel catalytic reaction using nickel, which is a far more naturally abundant transition metal. They first tackled the challenge in suppressing the formation of five-membered γ-lactams by harnessing the catalytic properties of nickel-hydride (NiH) species and the alkene dioxazolone substrate. High regioselectivity is achieved toward the desired formation of β-lactam scaffolds under this new catalytic system, whereby the NiH species react more favorably with the dioxazolone motif than with alkene to induce a β-selective carbon-nitrogen bond formation via nickel-amido intermediates. Enantioselective formation of chiral β-lactams has also become possible through combination with chiral ligands, which can be applied to the synthesis of biorelevant compounds. The researchers at IBS further demonstrated the value of their findings by simpliefied synthesis of a number of β-lactam compounds that previously required more complicated processes. Moreover, the produced β-lactams are estimated to have high market values up to 700 times in comparison to the starting raw materials, and the fact that this can be achieved using low-cost nickel catalyst makes this process highly economically desirable. What makes this development stand out is its immediate applicability. By employing this method, the team proposed more efficient and simplified synthesis strategies for specific medicines and natural substances. Moreover, they accomplished the synthesis of new compounds that can be potential drug candidates through late-stage functionalization of complex chemical structures. Director Chang commented, "Through this study, we were able to easily synthesize chiral β-lactam, the backbone of major antibiotics such as penicillin and carbapenem from cheap nickel catalysts and feedstock chemicals." He added, "Discovery of new pathways to synthesize high-value materials like chiral β-lactam is a significant achievement that can greatly shorten the drug discovery phase."

☝ 点击上方 一键预约 ☝   最新最热的医药健康新闻政策近日，由于台风影响，京津冀及东北地区遭遇了百年不遇的大雨，造成了城市的内涝及小范围内的洪涝灾害。大雨过后，往往是细菌真菌活跃的阶段，此时更容易产生病菌的感染，使人患病。此时，抗菌药就显得十分重要。那么，抗菌药物市场如何？近3年来，由于“限抗”政策的加压，疫情的影响，全身抗感染药物的市场规模较2019年有所下滑。其中以全身用抗真菌药占比最大，达抗感染品类的四分之一左右。图1 2017-2023Q1全身用抗感染药物品类情况（亿元）数据来源：中康CHIS图2  2017-2023Q1全身用抗真菌药物品类情况（亿元）数据来源：中康CHIS从细分品类来看，院内市场中头孢菌素类、青霉素类、β-内酰胺类抗菌药分别位列份额前三。院外市场零售终端中，青霉素类、头孢菌素类、大环内酯类&林可胺类和链阳菌素类排名前三。院内外略有差别，可能由于集采的影响。图3 2022年等级医院细分品类市场份额（%）数据来源：中康CHIS图4 2022年零售终端细分品类市场份额（%）数据来源：中康CHIS目前，国采已经进行到第八批，抗菌素作为重点采购对象，已有超50个品种的抗菌药纳入名单，剂型涵盖了口服常释剂型，如片剂、胶囊剂等，注射剂等等。执行集采后，部分品种销售额发生急速变化。如第五批集采中选品种注射用头孢他啶，自2021年出现大幅下滑。据中康CHIS所示，2021Q3注射用头孢他啶等级医院销售额10.19亿元，2021Q4“腰斩”仅为4.93亿元，2022年全年等级医院销售额仅为14.27亿元，不及2021年的35.26亿元的一半。表1 截止至第八批集采纳入的抗菌药数据来源：公开资料，中康产业研究院整理第九批国采将至，哪些全身抗菌药即将纳入集采成为大家关注的重点。综合原研+仿制大于5家的基本门槛及其他相关因素，本文列举了部分较有可能的品种。表2 第九批集采抗菌药预测数据来源：公开资料，中康产业研究院整理抗菌药目前存在的品种已相对饱和，新药研发更加趋向于针对“耐药性”和“安全性”的研发。由于多重耐药菌对传统常用的多种抗菌药均产生耐药性，容易无法达到治疗效果，延误病情。目前，迫切需要具有新机理或新结构的下一代抗菌药来解决这些问题，这一需求是长期的刚性需求。严重的感染通常发生在身体基础条件较差的患者身上，这类患者往往伴随着多种其他疾病。因此，研发不良反应较小的抗菌剂也成为药物研发的又一方向。此外，抗菌药方便携带及使用十分重要，更便于患者的服用，也减小医院的负担。新型口服剂型成为新剂型开拓的重点。(来源:新康界  作者:六爻）药闻康策新媒体矩阵微信公众号点击下方  一键关注  【免责声明】1.“药闻康策”部分文章信息来源于网络转载是出于传递更多信息之目的，并不意味着赞同其观点或证实其内容的真实性。如对内容有疑议，请及时与我司联系。2.“药闻康策”致力于提供合理、准确、完整的资讯信息，但不保证信息的合理性、准确性和完整性，且不对因信息的不合理、不准确或遗漏导致的任何损失或损害承担责任。3.“药闻康策”所有信息仅供参考，不做任何商业交易或医疗服务的根据，如自行使用“药闻康策”内容发生偏差，我司不承担任何责任，包括但不限于法律责任，赔偿责任。欢迎转发分享、收藏、点赞、点在看