We present the synthesis along with structural and photophysical properties of a series of 2‐(2′‐hydroxyphenyl)benzoxazole (HBO) and dimethylindole (HDMI) derivatives, in an effort to modulate their fluorescent properties by changing either electronic substitution or introducing planarization via ethynyl bridges. HBO and HDMI dyes are reported to undergo excited‐state intramolecular proton transfer, leading to red‐shifted emission with typically low quantum yield in solution, owing to pronounced non‐radiative deactivation channels. Introducing electron acceptors, such as benzonitrile, emerges as an effective strategy to boost the radiative transitions in these systems. In this context, this study aims at building structure–property relationships by a stepwise investigation of the influence of several parameters, that is, the nature of proton acceptor heterocycle (HBO vs. HDMI), the presence of an ethynyl moiety, and the addition of substituents (CN vs. Me). In each case, the nature of the transition(s) involved in the optical profile was also investigated by theoretical calculations.

We describe the synthesis, photophysical properties, and ab initio calculations on a series of 2-(2'-hydroxyphenyl)benzazoles (HBX), functionalized by a benzonitrile, prone to boost the fluorescent quantum yield in solution. HBX are well known to display the excited-state intramolecular proton transfer (ESIPT) process, but they typically lead to a quenched fluorescence in solution. The additional insertion of an ethynyl-triisopropylsilane substituent in the vicinity of the benzonitrile group acts as a cooperative moiety to obtain strong multiple-state emissive transitions with distinct emission wavelengths. Quantum yields of the ESIPT transition are up to 52% in solution, which are among the record values in the literature. The photophysical data can be further modulated by the nature of the heteroatom constitutive of HBX, paving the way for the development of ultrasensitive ratiometric probes.

This article describes the synthesis, along with comprehensive photophysical and ab initio characterization, of a series of 2-(2 '-hydroxyphenyl)benzoxazole (HBO) fluorophores, a family of compounds prone to undergoing an excited-state intramolecular proton transfer (ESIPT) process, functionalized with different positional isomers of quinoline or isoquinoline. We notably show that the position of the nitrogen atom at the azaheterocycle site has a key influence on both the emission profile and the photoluminescence quantum yield in solution. We also demonstrate the proton-sensitive nature of these dyes in solution, where not only does protonation trigger fluorescence enhancement, but it also acts as a transition switch between two excited states, with different emission profiles. HBO-isoquinoline displays very intense fluorescence not only in neutral and protonated dichloromethane solutions in the green-yellow region, but also in the solid state. Moreover, this dye exhibited a record Stokes shift of 11 000 cm-1.

This article describes the synthesis along with full photophysical characterization in both solution and solid-state of a series of 2-(2 '-hydroxyphenyl)benzazole linked to an aza-heterocycle (pyridine or isoquinoline) by one or two aryl rings. The impact of the length of the spacer is investigated in the light of emission wavelength, quantum yield, sensitivity to protons and possibility of transition switch upon protonation. Correlation of first-principle calculations and experimental results help decipher the excited-state dynamics, allowing to draw and discuss hypotheses concerning the nature of the excited species.

In this article, it describes the synthesis of a series of fluorophores consisting of N-alkyl or N-aryl pyridinium groups connected at different positions of a 2-(2'-hydroxyphenyl)benzoxazole scaffold and the exploration of the photophysical properties in solution (dichloromethane) and in the solid state, as amorphous powders. All dyes display a bathochromically shifted fluorescent transition from an excited keto state, formed after excited-state intramolecular proton transfer process. A full chemical engineering study was performed by changing the nature of the substitution at the pyridinium site (alkyl or aryl), the position of the pyridinium substitution and the nature of the counterion (six examples). The nature of the radiative transitions observed in these fluorescent dyes was confirmed by Time-dependent density functional theory (TD-DFT) calculations.

This letter describes the synthesis and structural, photophysical, and theoretical properties of novel fluorescent dyes derived from 2-(2'-hydroxyphenyl)benzoxazole, functionalized by tricyanofuran or α-cyano-γ-lactone groups, prone to undergo an excited-state intramolecular proton transfer (ESIPT) process. We serendipitously found that tricyanofuran can induce the formation of the corresponding lactone in basic media, leading to a highly fluorescent derivative, owing to the formation of a merocyanine in the excited state.

This article reports the synthesis, along with structural and photophysical characterization of 2-(2'-hydroxyphenyl)benzazole derivatives functionalized with various azaheterocycles (pyridine, pyrimidine, terpyridine). These compounds show dual-state emission properties, that is intense fluorescence both in solution and in the solid-state with a range of fluorescent color going from blue to orange. Moreover, the nature of their excited state can be tuned by the presence of external stimuli such as protons or metal cations. In the absence of stimuli, these dyes show emission stemming from anionic species obtained after deprotonation (D* transition), whereas upon protonation or metal chelation, ESIPT process occurs leading to a stabilized and highly emissive K* transition. With the help of extensive ab initio calculations, we confirm that external stimuli can switch the nature of the transitions, making this series of dyes attractive candidates for the development of stimuli-responsive fluorescent ratiometric probes.

Visible-light-operated photoswitches are of growing interest in reversibly controlling molecular processes, enabling for example the precise spatiotemporal focusing of drug activity and manipulating the properties of materials. Therefore, many research efforts have been spent on seeking control over the (photo)physical properties of photoswitches, in particular the absorption maxima and the half-life. For photopharmacological applications, photoswitches should ideally be operated by visible light in at least one direction, and feature a metastable isomer with a half-life of 0.1-10 seconds. Here we present our efforts towards the engineering of the half-life of iminothioindoxyl (ITI) photoswitches, a recently discovered class of visible-light-responsive photochromes, whose applicability was hitherto limited by half-lives in the low millisecond range. Through the synthesis and characterization of a library of ITI photoswitches, we discovered variants with a substantially increased thermal stability, reaching half-lives of up to 0.2 seconds. Based on spectroscopic and computational analyses, we demonstrate how different substituent positions on the ITI molecule can be used to tune its photophysical properties independently to fit the desired application. Additionally, the unique reactivity of the ITI derivative that featured a perfluoro-aromatic ring and had the most long-lived metastable state was shown to be useful for labeling of nucleophilic functional groups. The present research thus paves the way for using ITI photoswitches in photopharmacology and chemical biology.

We describe the synthesis, full photophysical study, and ab initio calculations of 2-(2'-hydroxyphenyl)benzazole (HBX) fluorophores substituted, at the meta position of the phenol group, by pyridine derivatives. HBX are commonly used as model dyes to study the stimuli-induced modulation of the Excited State Intramolecular Proton Transfer (ESIPT) process. The meta-substituted fluorophores reported herein, display a photophysical profile different from the previously reported ortho- and para-substituted HBO pyridine isomers. Indeed, while all dyes undergo spontaneous deprotonation in neutral conditions, leading to highly emissive anionic species; upon protonation, ortho- and para-pyridine substitution leads to resonance-stabilized keto isomers, formed after ESIPT. Protonated meta derivatives, unable to stabilize their excited structure by such electronic delocalization process, display sizable intramolecular charge transfer (ICT) processes, translating into significantly redshifted emission. In addition, all dyes present a strong emission intensity, not only in neutral and acidic solutions, but also in the solid-state. The nature of the emissive transitions was confirmed in each case by theoretical calculations combining Time-Dependent Density Functional Theory (TD-DFT) and second-order Coupled Cluster (CC2) methods. This article describes the synthesis, photophysical studies, and ab initio calculations of 2-(2'-hydroxyphenyl)benzazole (HBX) fluorophores substituted, at the meta position of the phenol group, by pyridine derivatives. As opposed to previously reported positional isomers, these meta-substituted fluorophores display sizable intramolecular charge transfer (ICT) processes, in their protonated state translating into significantly redshifted emission. The nature of the emissive transitions was confirmed by theoretical calculations combining Time-Dependent Density Functional Theory (TD-DFT) and second-order Coupled Cluster (CC2) methods. image

Chemical reactions are central for the creation of new materials, drug design and many more fields. Obtaining high reaction yields is of great importance to reduce cost and increase the efficiency and purity of the obtained product. To reduce the number of experiments for high reaction yield screening in organic chemistry, the use of active learning (AL) is an interesting approach. Unfortunately, the majority of AL is based on "retro-AL" where all the reactions are already available. One problem of "real-time" AL is determining when to stop the AL loop without creating an external labeled test set to analyze the performance of the model. The stopping procedure presented in this work is a stopping criterion, namely the stabilization prediction (SP) (Bloodgood et al., Proceedings of the Thirteenth Conference on Computational Natural Language Learning, 2009, 39-47). It uses an unlabeled equivalent of a test set called a stop set to indirectly evaluate the accuracy of the AL loop. To benchmark the stability of this method and investigate its applicability in chemistry, two datasets from the organic literature, four estimators, three types of descriptors, two sizes of queries per iteration (QPI) and stop set size were investigated. We determine that the present method is the most stable with a Support Vector Classification (SVC) estimator, 50 QPI and a stop set size containing 30% of the data. It produces the best compromise between an early stop (consumes less than 50% of the data) and a reliable accuracy over 10 different runs compared to the accuracy obtained with classical supervised machine learning. We do hope that this method would be of use to create "real-time" AL in chemistry. Chemical reactions are central for the creation of new materials, drug design and many more fields.

Excited-State Intramolecular Proton Transfer (ESIPT) emission is associated with intense single or multiple fluorescence in the solid-state, along with enhanced photostability and sensitivity to the close environment.

Azonium ions formed by the protonation of tetra-ortho-methoxy-substituted aminoazobenzenes photoisomerize with red light under physiological conditions. This property makes them attractive as molecular tools for the photocontrol of physiological processes, for example, in photopharmacology. However, a mechanistic understanding of the photoisomerization process and subsequent thermal relaxation is necessary for the rational application of these compounds as well as for guiding the design of derivatives with improved properties. Using a combination of sub-ps/ns transient absorption measurements and quantum chemical calculations, we show that the absorption of a photon by the protonated E-H+ form of the photoswitch causes rapid (ps) isomerization to the protonated Z-H+ form, which can also absorb red light. Proton transfer to solvent then occurs on a microsecond time scale, leading to an equilibrium between Z and Z-H+ species, the position of which depends on the solution pH. Whereas thermal isomerization of the neutral Z form to the neutral E form is slow (∼0.001 s-1), thermal isomerization of Z-H+ to E-H+ is rapid (∼100 s-1), so the solution pH also governs the rate at which E/E-H+ concentrations are restored after a light pulse. This analysis provides the first complete mechanistic picture that explains the observed intricate photoswitching behavior of azonium ions at a range of pH values. It further suggests features of azonium ions that could be targeted for improvement to enhance the applicability of these compounds for the photocontrol of biomolecules.

Insect nicotinic acetylcholine receptors (nAChRs) are a recognized target for insecticide design. In this work, we have identified, from a structure-based approach using molecular modeling tools, ligands with potential selective activity for pests versus pollinators. A high-throughput virtual screening with the Openeye software was performed using a library from the ZINC database, thiacloprid being used as the target structure. The top sixteen molecules were then docked in α6 cockroach and honeybee homomeric nAChRs to check from a theoretical point of view relevant descriptors in favor of pest selectivity. Among the selected molecules, one original sulfonamide compound has afterward been synthesized, together with various analogs. Two compounds of this family have been shown to behave as activators of the cockroach cholinergic synaptic transmission

We detail the synthesis of a series of fluorophores containing triphenylamine derivatives along with their photophysical, electrochemical, and electronic structure properties. These compounds include molecular structures derived from imino-phenol (anil) and hydroxybenzoxazole scaffolds originating from similar salicylaldehyde derivatives and display excited-state intramolecular proton transfer. We show that depending on the nature of the π-conjugated scaffold, different photophysical processes are observed: aggregation-induced emission or dual-state emission, with a modulation of the fluorescence color and redox properties. The photophysical properties are further rationalized with the help of ab initio calculations.

A series of pyrroloquinolone photosensitizers bearing different halogen substituents (Cl, Br, I) on the heterocyclic framework was studied. These structures were readily prepared through a multi-step synthetic sequence involving an oxidative protocol as an important step to access the quinolone framework. Spectroscopic characterizations and computational investigations were carried out to study the dyes before and after the oxidative step. Interestingly, the fluorescence emission was significantly reduced upon oxidation. In spite of a low photostability under UV light, the pyrroloquinolone photosensitizers proved effective to produce singlet oxygen. Higher singlet oxygen quantum yields were obtained with photosensitizers bearing halogen atoms with a higher atomic number.

Improving the armamentarium to treat invasive candidiasis has become necessary to overcome drug resistance and the lack of alternative therapy. In the pathogenic fungus Candida albicans, the 90-kDa Heat-Shock Protein (Hsp90) has been described as a major regulator of virulence and resistance, offering a promising target. Some human Hsp90 inhibitors have shown activity against Candida spp. in vitro, but host toxicity has limited their use as antifungal drugs. The conservation of Hsp90 across all species leads to selectivity issues. To assess the potential of Hsp90 as a druggable antifungal target, the activity of nine structurally unrelated Hsp90 inhibitors with different binding domains was evaluated against a panel of Candida clinical isolates. The Hsp90 sequences from human and yeast species were aligned. Despite the degree of similarity between human and yeast N-terminal domain residues, the in vitro activities measured for the inhibitors interacting with this domain were not reproducible against all Candida species. Moreover, the inhibitors binding to the C-terminal domain (CTD) did not show any antifungal activity, with the exception of one of them. Given the greater sequence divergence in this domain, the identification of selective CTD inhibitors of fungal Hsp90 could be a promising strategy for the development of innovative antifungal drugs.

UnaG is a new class of fluorescence protein in which an endogenous ligand, namely bilirubin (BLR), plays the role of chromophore. Upon photoexcitation, holoUnaG emits green light. A single mutation at residue 57 induces a decrease in the fluorescence quantum yield. To our knowledge, no atomic simulation at the atomic level has been carried out to date to explain this fluorescence decay in N57A and N57Q mutants. Herein molecular dynamics simulations were carried out on wild-type (WT) UnaG and both mutants to investigate the structural impact of the mutation on its global structure, on BLR and the absorption spectra. Our study reveals significant global changes upon mutation at the protein entrance (L3, H2, and, H3) governing a BLR modification. BLR in WT UnaG is rather rigid while when embedded into N57A or N57Q, dihedral angles between endo and exo vinyl moieties and between A and B rings at the entrance of UnaG are strongly modified along with the number of inter-/intramolecular interactions. The water molecules play an important role in the modification of the shape of the binding cavity. For the first time, we show that the structural modifications upon ligand mutations are tightly related to the key structural changes in the protein such as Loop3 (L3), β sheet 2 (B2), and β sheet 3 (B3) dynamics. The present work suggests that the quenching of the fluorescence properties of UnaG mutants is mainly a non-radiative process closely related to the BLR flexibility induced by global structural changes.

RAD51 is a pivotal protein of the homologous recombination DNA repair pathway, and is overexpressed in some cancer cells, disrupting then the efficiency of cancer-treatments. The development of RAD51 inhibitors appears as a promising solution to restore these cancer cells sensitization to radio- or chemotherapy. From a small molecule identified as a modulator of RAD51, the 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), two series of analogues with small or bulky substituents on the aromatic parts of the stilbene moiety were prepared for a structure-activity relationship study. Three compounds, the cyano analogue (12), and benzamide (23) or phenylcarbamate (29) analogues of DIDS were characterized as novel potent RAD51 inhibitors with HR inhibition in the micromolar range.

Human granzyme B (hGzmB), which is present in various immune cells, has attracted much attention due to its role in various pathophysiological conditions. The hGzmB activity is triggered at a catalytic triad (His59, Asp103, Ser198), cleaving its specific substrates. To date, the drug design strategy against hGzmB mainly targets the catalytic triad, which causes the non-specificity problem of inhibitors due to the highly conserved active site in serine proteases. In the present work, microsecond classical molecular dynamics simulations are devoted to exploring the structural dynamics of the hGzmB catalytic cycle in the presence of Ac-IEPD-AMC, a known substrate (active hGzmB), and Ac-IEPD-CHO, a known inhibitor (inactive hGzmB). By comparing active and inactive forms of hGzmB in the six different stages of the hGzmB catalytic cycle, we revealed, for the very first time, an additional network of interactions involving Arg216, a residue located outside the conventional binding site. Upon activation, the His59∙∙∙Asp103 hydrogen bond is broken due to the formation of the Asp103∙∙∙Arg216 salt bridge, expanding the active site to facilitate the substrate-binding. On the contrary, the binding of inhibitor Ac-IEPD-CHO to hGzmB prevents the Arg216-mediated interactions within the catalytic triad, thus preventing hGzmB activity. In silico Arg216Ala mutation confirms the role of Arg216 in enzyme activity, as the substrate Ac-IEPD-AMC failed to bind to the mutated hGzmB. Importantly, as Arg216 is not conserved amongst the various granzymes, the current findings can be a major step to guide the design of hGzmB specific therapeutics.

We describe various synthetic pathways to introduce sterically hindered substituents (mesityl, 2,4,6‐triisopropylphenyl, anthracene) to the proton donor side of excited‐state intramolecular proton transfer (ESIPT)‐capable 2‐(2’‐hydroxyphenyl) benzoxazole (HBO) fluorophores. Two original synthetic approaches were investigated in order to synthesize seven HBO derivatives. Optimization studies concluded that electron rich and bulky phosphine ligands are required to ensure completion of the Suzuki‐Miyaura cross‐coupling reaction involving a bulky aromatic boronic acid. The photophysical properties of all dyes revealed a strong influence of the nature of the solvent on the optical properties, as protic solvents tend to stabilize enol tautomers and induce dual emission. Our studies confirmed that, unlike the majority of organic dyes, ESIPT fluorophores do not undergo π‐stacking in the solid‐state. The nature of the excited‐states was explored by ab initio calculations.