Sarabindu Roy (TCGLS Member), Ajay Yadaw (TCGLS Member), Subho Roy (TCGLS Member), Gopal Sirasani (TCG GC Member), Aravind Gangu (TCG GC Member), Jack D. Brown (TCG GC Member), Joseph D. Armstrong III (TCG GC Member), Rodger W. Stringham, B. Frank Gupton, Chris H. Senanayake* (TCG GC Member), and David R. Snead*Organic Process Research and Development (Published on 07th Jan 2022)
DOI: https://doi.org/10.1021/acs.oprd.1c00071
Abstract: Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.
Priyadarshi Manna (TCGLS Member); Mrinalkanti Kundu (TCGLS Member); Ashis Roy (TCGLS Member);Susanta Adhikari
DOI : https://doi.org/10.1039/D1OB00663K
Abstract: The synthesis of deuterium-labeled organic compounds is of increased interest, especially after the approval of deutetrabenazine by the Food and Drug Administration in 2014. The selective incorporation of deuterium in the place of hydrogen not only represents uniqueness in terms of a novel chemical class, but it also can improve the pharmacokinetic profiles of drug molecules while retaining potency and other parameters; thus, hydrogen–deuterium (H/D) exchange methods have been proven to be powerful additions in different areas of chemical science. In that regard, metal-catalyzed deuterium labeling via C–H activation mediated by a unique inbuilt directing group (DG) can play a significant role in the synthesis of novel deuterated chemical entities. In this context, herein, we divulge our results relating to Pd(II)-catalyzed deuterium incorporation (>97%) at the γ C(sp2)-position of pyridone-containing phenylacetic acid derivatives, where 3-amino-1-methyl-1H-pyridin-2-one (AMP) not only acts as an efficient N,O-directing group, but it also constitutes a part of the target molecules of medicinal importance. Our methodology, which has been optimized based on the effects of temperature, catalyst, time, and substrate scope, shows advantages over existing protocols, with non-selectivity or meager deuteration or the use of an expensive metal (catalytic or super stoichiometric) and a deuterated solvent, reported previously for the deuteration of phenylacetic acid and its derivatives. Moreover, towards our aim of synthesizing deuterium-labeled biologically relevant compounds, the gram scale synthesis of a deuterated analogue of biphenyl acetic acid (3), known to have activity against epileptic seizures, has also been successfully accomplished in high yields and with excellent isotope enrichment via implementing this protocol.
DOI : https://doi.org/10.1021/acs.joc.1c00124
Abstract: Org. transformations exclusively in water as an environmentally friendly and safe medium have drawn significant interest in the recent years. Moreover, transition metal-free synthesis of enantiopure mols. in water will have a great deal of attention as the system will mimic the natural enzymic reactions. In this work, a new set of proline-derived hydrophoborganocatalysts have been synthesized and utilized for asym. Michael reactions in water as the sole reaction medium. Among the various catalysts screened, the catalyst 1 is indeed efficient for stereoselective 1,4-conjugated
Michael addns. (dr: >97:3, ee up to >99.9%) resulting in high chem. yields (up to 95%) in a very short reaction time (1 h) at room temp. This methodol. provides a robust, green, and convenient protocol and can thus be an important addn. to the arsenal of the asym. Michael addn. reaction. Upon successful implementation, the present strategy also led to the formation of an optically active octahydroindole, the key component found in many natural products.
Graphical Abstract:-
Authors: Chandan K Mahato (TCGLS Member); Satan Mukherjee, Mrinalkanti Kundu* (TCGLS Member); Virbhadra P. Vallapure, Animesh Pramanik
Biswajit Mondal (TCGLS Member); Prasanjit Ghosh; Mrinalkanti Kundu; (TCGLS Member); Sajal Das
DOI : https://doi.org/10.1039/D0OB02510K
Abstract: We demonstrate herein the first example of a palladium(II) catalyzed regioselective ortho-C(sp2)–H arylation in aqueous medium (a sustainable solvent) utilizing 8-AIP (8-aminoimidazo[1,2-a]pyridine) as a promising and removable bidentate directing group/auxilliary. This newly developed protocol features a broad substrate scope with excellent functional group tolerance and enables an expeditious route to a library of unsymmetrical amides in good to excellent yields with exclusive site-selectivity
Published in: Journal, Article, Research Support, Non-U.S. Gov’t Volume : 16, Issue : 3, Pages : 484-498
DOI : 10.1002/cmdc.202000564
Author : Yasmin, Sabina; Cerchia, Carmen; Badavath, Vishnu Nayak; Laghezza, Antonio; Dal Piaz, Fabrizio; Mondal, Susanta K.; Atli, Oezlem; Baysal, Merve; Vadivelan, Sankaran; Shankar, S.; Siddique, Mohd. Usman Mohd.; Pattnaik, Ashok Kumar; Singh, Ravi Pratap; Loiodice, Fulvio; Jayaprakash, Venkatesan; Lavecchia, Antonio
Abstract : Insulin resistance is a major pathophysiol. feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their mol. target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds (I) and (II) bound PRDX1 and induced a dose-dependent inhibition. Furthermore, I and II significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathol. examinations These results provide guidance for developing the current FAAs as new potential antidiabetic agents.
Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 64, Issue : 1, Pages : 840-844
DOI : 10.1021/acs.jmedchem.0c01793
Author : Preston, Sarah; Garcia-Bustos, Jose; Hall, Liam G.; Martin, Sheree D.; Le, Thuy G.; Kundu, Abhijit; Ghoshal, Atanu; Nguyen, Nghi H.; Jiao, Yaqing; Ruan, Banfeng; Xue, Lian; Huang, Fei; Chang, Bill C. H.; McGee, Sean L.; Wells, Timothy N. C.; Palmer, Michael J.; Jabbar, Abdul; Gasser, Robin B.; Baell, Jonathan B.
Abstract : A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indexes, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.
DOI: https://doi.org/10.1039/D0OB02134B
Palladium catalyzed arylation of the inert β-C(sp2)–H bond of carboxylic acid derivatives is reported herein for the first time utilizing 8-aminoimidazo[1,2-a]pyridine (AIP) as an efficacious and new inbuilt 6,5-fused bicyclic removable directing group. This protocol is scalable, exhibits high levels of β-site selectivity and tolerates a broad spectrum of functional groups.
Authors: Biswajit Mondal (TCGLS Member), Prasanjit Ghosh, Mrinalkanti Kundu* (TCGLS Member), Tapas Kumar Das (TCGLS Member), Sajal Das*
Authors: Tanmay K. Pati (TCGLS Member), Sk Ajarul, Mrinalkanti Kundu (TCGLS Member), Deepak Tayde, Uttam Khamrai (TCGLS Member),* and Dilip K. Maiti*
DOI: https://doi.org/10.1021/acs.joc.0c00941
We have identified different N-substituted 2-pyridones as inbuilt directing groups for selective C–H-activated functionalization instead of deprotecting and/or throwing away the directing groups. A robust general method for external ligand-free PdII-catalyzed C¬(sp2)–H olefination and alkynylation is established to access valuable phenylacetamido-2-pyridones. Diverse substrate scope has been demonstrated with 48 different examples with high yield and gram-scale synthesis. Adequate tolerance of valuable functional groups was also observed, such as olefins possessing esters, sulfone, amide, cyanide, and ketones, aromatic residues containing fluorine, chlorine, bromine, NO2, methyl, dimethyl, and methoxy, as well as 2-pyridone-N-bearing methyl, cyclopropyl methyl, cyclopentyl methyl, benzyl, phenyl, acetate, and acetamide groups, which smoothly produced the respective desired products. We used triisopropyl silane-substituted alkynes for the alkynylation reaction, which can easily be converted to several functional groups including terminal alkyne, heterocycle through click reaction, and others. Implementing our protocol, we have also demonstrated late-stage olefination and alkynylation of 2-pyridone, containing the CB2 agonist-type molecule with excellent yield. Considering N-substituted 2-pyridone acts as a biologically-active structural unit, this general method has the significance in terms of late-stage functionalization to access new molecular entities which can be employed in medicinal chemistry research through diverse C–H activation.
Authors : Rishi Das [TCGLS Member], Tathagata Sengupta [TCGLS Member], Shubhrajit Roy, Sumantra Chattarji, Jharna Ray
DOI: 10.1097/WNR.0000000000001446
The memory-boosting property of Indian traditional herb, Convolvulus pluricaulis, has been documented in literature; however, its effect on synaptic plasticity has not yet been reported. Two important forms of synaptic plasticity known to be involved in the processes of memory formation are long-term potentiation (LTP) and long-term depression (LTD). In the present study, the effect of C. pluricaulis plant extract on LTP and LTD were evaluated. The adult male Wistar rats were fed orally with 250, 500 and 1000 mg/kg of this extract for 4 weeks and the effect was determined on LTP and LTD in the Schaffer collaterals of the hippocampal cornu ammonis region CA1. We found that the 500 mg/kg dose of the extract could significantly enhance LTP compared to the vehicle treated ones. Moreover, the same dose could also reduce LTD while used in a separate set of animals. Also, a fresh group of animals treated with the effective dose (500 mg/kg) of plant extract were examined for memory retention in two behavioral platforms namely, contextual fear conditioning (CFC) and novel object recognition test (NORT). Increased fear response to the conditioned stimulus and enhanced recognition of objects were observed in CFC and NORT, respectively, both indicating strengthening of memory. Following up, ex-vivo electrophysiology experiments were performed with the active single molecule scopoletin, present in C. pluricaulis extract and similar patterns in synaptic plasticity changes were obtained. These findings suggest that prolonged treatment of C. pluricaulis extract, at a specific dose in healthy animals, can augment memory functions by modulating hippocampal plasticity..
Ashis Roy (TCGLS Member), Dr. Mrinalkanti Kundu (TCGLS Member), Dr. Pranab Dhar (TCGLS Member), Arnish Chakraborty (TCGLS Member), Dr. Soumen Mukherjee (TCGLS Member), Jayatri Naskar (TCGLS Member), Dr. Chhanda Rarhi (TCGLS Member), Dr. Rajib Barik (TCGLS Member), Dr. Susanta Kumar Mondal (TCGLS Member), Mushtaq Ahmad Wani, Rahul Gajbhiye, Prof. Kuldeep K. Roy, Dr. Arup Maiti (TCGLS Member), Priyadarshi Manna (TCGLS Member), Prof. Susanta Adhikari
DOI : https://doi.org/10.1002/slct.202000208
Abstract
A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized, and characterized. In vitro anti‐proliferative activity of the synthesized compounds was evaluated against six different human cancer cell lines using MTT assay. Among all twenty-four compounds tested, compound 22 (N‐([1,1′‐biphenyl]‐4‐yl)‐2‐((3‐methyl‐4‐oxo‐6,7,8,9‐tetrahydro‐4Hpyrido[1,2‐a]pyrimidin‐2‐yl)oxy)acetamide) exhibited significant cell growth inhibition of human liver cancer cells HepG2 with GIC50 (50% growth inhibitory concentration) value of 120+10 nM and was found to be selective over healthy human embryonic kidney (HEK) cell line (33.1% inhibition at 20 μM). Further studies demonstrated that compound 22 induced cell apoptosis in HepG2 cells and resulted in a similar effect to Staurosporine, a well known proapoptotic compound widely used to induce apoptosis in various cancer cell lines. Compound 22 also rendered acceptable aqueous solubility (3.5+0.37 μM, at pH 7.4) and attractive metabolic stability against human liver microsomes with a half‐life of 34.63+0.33 minutes. Based on the similarity observed between the known tankyrase‐1 inhibitors available in the literature and compound 22, in silico docking study was performed and the results suggested that the compound interacted with the key amino acid residues present in the tankyrase‐1 enzyme active site.
.jpg ?>)
.jpg ?>)
