Delving into the Latest Updates on Integral BioSciences Pvt. Ltd. with Synapse

BACKGROUNDBuspirone is a critical in treatment for generalized anxiety disorder (GAD), but the synthesis of its key intermediate, 2-(piperazin-1-yl) pyrimidine faces challenges in terms of cost, yield and purity. Traditional synthesis methods are hindered by high material costs and significant by-product formation, necessitating a more efficient and economical approach.OBJECTIVETo develop a novel, cost-effective synthesis strategy for the 2-(piperazin-1-yl) pyrimidine intermediate that improves yield and purity while reducing production costs and environmental impact.METHODSA four-step synthesis process was optimized as follows: First, piperazine reacts with sulfuric acid and cyanamide, followed by precipitation with cold methanol. Next, 1,1,3,3-tetramethoxypropane reacts with hydrochloric acid and amidine, and the mixture was extracted with dichloromethane (DCM). In the third step, the product was dissolved in isopropanol (IPA), treated with charcoal and converted to the oxalate salt using oxalic acid. Finally, the oxalate salt was converted to the freebase with ammonia, followed by a final extraction with DCM. Key variables such as reagent equivalents, reaction conditions and purification techniques were systematically optimized throughout the process.RESULTSThe optimized process achieved a purity level of over 99% and reduced production costs by 25-30%. Significant improvements included controlled bis-product formation with cyanamide, effective addition of 1,1,3,3-tetramethoxypropane and efficient removal of by-products through oxalate salt formation and charcoal treatment.CONCLUSIONThe developed synthesis method for 2-(piperazin-1-yl) pyrimidine was both cost-effective and efficient, significantly enhancing the yield and purity. This method is highly suitable for large-scale pharmaceutical production, aligning with industry goals of improved process efficiency, cost reduction and environmental sustainability.

2025-03-01·Synlett

Development of New N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide Analogues: Exploring Anticancer Potential through MerTK Inhibition

作者: Murti, Yogesh ; Meenakshi, Meenakshi ; Mahajan, Shriya ; Murti, Yogesh ; Sathe, Balaji Dashrath ; Rathod, S. V. ; Mahajan, Shriya ; Goel, Kapil Kumar ; Meenakshi, Meenakshi ; Mane, Madhav Shivaji ; Rathod, S. V. ; Kandhari, Harsimrat ; Pandey, Sarvesh Kumar ; Dwivedi, Ashish Ranjan ; Goel, Kapil Kumar ; Pandey, Sarvesh Kumar ; Kandhari, Harsimrat ; Rawat, Pramod ; Mane, Madhav Shivaji ; dwivedi, ashish ranjan

AbstractMer proto-oncogene tyrosine-protein kinase (MerTK), a part of the TAM (TYRO3, AXL, and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor is a promising strategy for more-effective chemotherapy. Considering the pharmacophoric features of the active domain of MerTK and the structural characteristics of the investigational drug BMS794833, we designed five new N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide analogues. In cytotoxicity studies, one of the analogues displayed a significantly higher cytotoxicity than cisplatin. It showed IC50 values of 2.09, 1.96, and 3.08 μM against A549, MCF-7, and MDA-MB-231 cancer cell lines, respectively. In drug metabolism and pharmacokinetic studies, it was the most stable analogue and displayed a moderate MerTK inhibitory potential. Molecular-docking studies were performed to corroborate the MerTK inhibition, and the same analogue achieved the most significant docking score (–12.33 kcal/mol). Docking interactions demonstrated that the imine and amine group of the 3-chloropyridine moiety of BMS794833 formed hydrogen bonds with the main chain of the ATP pocket residue Met674, while the oxygen atoms of the 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with the Lys619 and Asp741 amino acid residues of the allosteric pocket of MerTK protein. These promising results provide evidence that the N-{4-[(7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide pharmacophore can give potential insights into the development of new MerTK inhibitors.

2024-12-01·Chemical Biology & Drug Design

Design and Development of Novel Hybrids Based on Pyrrolo[2,1‐f][1,2,4]Triazine and 1‐(Methylpiperidin‐4‐yl) Aniline–Based Analogs: Exploring the Utility as Anticancer Agents via MERTK Inhibition

Article

作者: Singh, Thakur Gurjeet ; Rawat, Pramod ; Nainwal, Nidhi ; Sathe, Balaji Dashrath ; Jaiswal, Shivani ; Kumar, Devendra ; Kumar, Bhupinder ; Dwivedi, Ashish Ranjan ; Yadav, Savita ; Rathod, S. V.

ABSTRACTMer‐tyrosine kinase (MERTK), a member of the AXL, TYRO3, and MERTK (TAM) family, is one of the promising targets for cancer treatment. It plays a key role in cancer cell survival and proliferation and regulates immune responses in cancer. The study aimed to rationally design and develop molecules considering the pharmacophoric requirements of MERTK using a multi‐synthetic approach followed by the hybridization of individual pharmacophores. A hybrid drug design approach was employed by hybridization of pyrrolo[2,1‐f][1,2,4]triazine and 1‐(methylpiperidin‐4‐yl)aniline pharmacophoric systems to develop novel leads (1K1–1K5). The molecules were synthesized via a multi‐step synthetic approach. The synthesized molecules were assessed for their pharmacological potential via cell viability, drug metabolism and pharmacokinetics (DMPK), and MERTK inhibition studies corroborated by in silico studies. IK5 was found to have an IC50 value of 0.36 μM towards A549, followed by 0.42 μM and 0.80 μM against MCF‐7 and MDA‐MB‐231 cells, respectively. Further, the molecules were also analyzed for their microsomal stability and were found to be stable with better intrinsic clearance profiles. The molecules thus pave a strategy for developing novel MERTK inhibitors and their advance in vitro and in vivo assessment in the future.

100 项与 Integral BioSciences Pvt. Ltd. 相关的药物交易

登录后查看更多信息

100 项与 Integral BioSciences Pvt. Ltd. 相关的转化医学

登录后查看更多信息