163 research outputs found
Click 1,2,3-triazoles in drug discovery and development: From the flask to the clinic?
No full textAfter 20 years since its conception, click chemistry has come of age and we believe the time has come to evaluate if the copper-catalyzed azide alkyne cycloaddition (CuCAAC) reaction deserves to be considered the perfect transformation in medicinal chemistry campaigns and to weigh up the concrete results that have been produced in terms of drugs approved and clinical candidates in development. After a description of the properties of the triazole nucleus in terms of both pharmacokinetic and pharmacodynamic profile, a practical guide for the best approaches to be used for the synthesis of triazoles is provided, capitalizing on our 20-year hands-on experience in this chemistry. Finally, we describe those molecules displaying the 1,2,3-triazole nucleus that have entered the market or are, at least, in clinical trials. Only four 1,2,3-triazole-bearing drugs have been launched so far. Among them the recently approved antibody drug conjugate sacituzumab govitecan was discovered thanks to click chemistry. Nevertheless, to the best of our knowledge, there are a dozen 1,2,3-triazoles in clinical development and it is likely that we will witness the launch on the market of at least some of them, encouraging medicinal chemists to further use this approach, not only as a route to early-stage discoveries, but also as a means to developing successful drugs
Deuterium in drug discovery: progress, opportunities and challenges
No full textSubstituting a hydrogen atom with its heavy isotope deuterium may improve the pharmacokinetic and/or toxicity profile of a drug compared with its non-deuterated counterpart. This article highlights milestones in the field of deuteration in drug discovery and development, and discusses recent examples of its application, which have shifted towards deuteration of novel drug candidates instead of developing deuterated analogues of marketed drugs.Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed
Transition-Metal-Free Synthesis of 2-Arylimidazolones via Cascade Reaction between Arynes and α,α′-Disubstituted α-Isocyanoacetamides
No full textThe reaction between arynes and secondary α,α′-disubstituted α-isocyanoacetamides was developed to access 2-arylimidazolones of structural diversity and complexity in a straightforward manner
FOURIER-TRANSFORM FAR-INFRARED SPECTROSCOPY OF ASTROPHYSICAL SPECIES
No full textO. Pirali, J. Orphal, M. Vervloet, J.-B. Brubach, P. Roy, international Symposium on Molecular Spectroscopy, Talk WH01, 2002.Author Institution: CNRS, Laboratoire de Photophysique Mol\'{e}culaire, Universit\'{e} Paris SudFIRST (Far InfraRed Space telescope) and ALMA (Atacama Large Millimeter Array) are future instruments wich will be used to study galaxies, star formation, interstellar medium, clouds These instruments will record spectra of such astrophysical objects in the far-infrared (FIR) spectral region . Laboratory measurements are therefore necessary to complete the spectroscopic knowledge of astrophysically important molecules in this spectral region. We have recorded, with our interferometer Bruker IFS-120 (maximum resolution: ), emission and absorption spectra of several astrophysical species in the FIR region. Thermal emission spectra of hot small molecules ( and its isotopomers) have been recorded as well as spectra of radicals () using different excitation sources. FIR emission spectroscopy (between 50 and ) of Polycyclic Aromatic Hydrocarbons (PAHs) has also been performed. We have detected the low frequency bending vibrations of the aromatic rings which are the fingerprints of the PAH molecules. The absorption spectrum of Naphtalene in the same spectral range leads to resolve the P, Q and R branches of these vibrational transitions. As already , the much brighter FIR continuum source provided by synchrotron radiation will be exploited for further improved absorption measurements
The 115 year old multicomponent Bargellini reaction: Perspectives and new applications
No full text: Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929-1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it
Tritylamine as an ammonia surrogate in the ugi reaction provides access to unprecedented 5-sulfamido oxazoles using burgess-type reagents
No full textStarting from a wide range of α-acylamino amide substructures synthesized using tritylamine as an ammonia surrogate in the Ugi reaction, Burgess-type reagents enable cyclodehydration and afford unprecedented oxazole scaffolds with four points of diversity, including a sulfamide moiety in the 5-position. The synthetic procedure employs readily available starting materials and proceeds smoothly under mild reaction conditions with good tolerance for a variety of functional groups, coming to fill a gap in the field of oxazole compounds
A rotational investigation of the three isomeric forms of cyanoethynylbenzene (HCC-C6H4-CN): benchmarking experiments and calculations using the “Lego brick” approach
No full textWe report the study of three structural isomers of phenylpropiolonitrile (3-phenyl-2-propynenitrile, C6H5-C3N) containing an alkyne function and a cyano group, namely ortho-, meta-, and para-cyanoethynylbenzene (HCC-C6H4-CN). The pure rotational spectra of these species have been recorded at room temperature in the millimeter-wave domain using a chirped-pulse spectrometer (75-110 GHz) and a source-frequency modulation spectrometer (140-220 GHz). Assignments of transitions in the vibrational ground state and several vibrationally excited states were supported by quantum chemical calculations using the so-called “Lego brick” approach [A. Melli, F. Tonolo, V. Barone and C. Puzzarini, J. Phys. Chem. A, 2021, 125, 9904-9916]. From these assignments, accurate spectroscopic (rotational and centrifugal distortion) constants have been derived: for all species and all observed vibrational states, predicted rotational constants show relative accuracy better than 0.1%, and often of the order of 0.01%, compared to the experimental values. The present work hence further validates the use of the “Lego brick” approach for predicting spectroscopic constants with high precision
What's in a Name? Drug Nomenclature and Medicinal Chemistry Trends using INN Publications
No full textThe World Health Organization assigns international nonproprietary names (INN), also known as common names, to compounds upon request from drug developers. Structures of INNs are publicly available and represent a source, albeit underused, to understand trends in drug research and development. Here, we explain how a common drug name is composed and analyze chemical entities from 2000 to 2021. In the analysis, we describe some changes that intertwine chemical structure, newer therapeutic targets (e.g., kinases), including a significant increase in the use of fluorine and of heterocycles, and some other evolutionary modifications, such as the progressive increase in molecular weight. Alongside these, small signs of change can be spotted, such as the rise in spirocyclic scaffolds and small rings and the emergence of unconventional structural moieties that might forecast the future to come
Synthesis, Docking and Biological Evaluation of a Novel Class of Imidazothiazoles as IDO1 Inhibitors
No full textIDO1, a key dioxygenase in tryptophan-kynurenine metabolism, appeared in the last 10 years at the vanguard of druggable targets in cancer therapy due to its well-established role both in immune escape and inflammatory neovascularization. Among the pool of IDO1 inhibitors that have entered clinical trials, none have reached approval. The identification of novel inhibitors endowed with better clinical profile, together with the further comprehension of the interactions with residues in IDO1 active site, are still a need. In this context, we have synthesized a novel class of imidazothiazole derivatives as IDO1 inhibitors and identified three compounds with inhibitory potency in the low micromolar range. This report strengthens the role played by pocket C in the active site of IDO1, providing novel directions in the design of IDO1 inhibitors
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