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Human cytomegalovirus (hCMV) is responsible for several pathologies impacting immunocompromised patients and can trigger life-threatening infection. Several antivirals are available and are used in the clinic, but hCMV resistant strains have appeared and patients have encountered therapeutic failure. Hence, there is a constant need for new best in class or first in class antiviral molecules. We have previously shown that nitrocorroles could be used as a potent anti-hCMV agent without acute toxicity in mice. They therefore represent an excellent platform to perform structure–activity relationship (SAR) studies and to increase efficiency or reduce toxicity. We have generated original A 2 B- and A 3 -substituted nitrocorroles and have discovered optimized compounds with selectivity indices above 200. These compounds are easily synthesized in only one to two-step reactions; they are up-scalable and cost efficient. They are therefore excellent candidates for hCMV therapies and they pave the way for a new generation of molecules.

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme (DUB), is a potential drug target in various cancers, and liver and lung fibrosis. However, bona fide functions and substrates of UCHL1 remain poorly understood. Herein, we report the characterization of UCHL1 covalent inhibitor MT16-001 based on a thiazole cyanopyrrolidine scaffold. In combination with chemical proteomics, a closely related activity-based probe ( MT16-205 ) was used to generate a comprehensive quantitative profile for on- and off-targets at endogenous cellular abundance. Both compounds are selective for UCHL1 over other DUBs in intact cells but also engage a range of other targets with good selectivity over the wider proteome, including aldehyde dehydrogenases, redox-sensitive Parkinson's disease related protein PARK7, and glutamine amidotransferase. Taken together, these results underline the importance of robust profiling of activity-based probes as chemical tools and highlight the cyanopyrrolidine warhead as a versatile platform for liganding diverse classes of protein with reactive cysteine residues which can be used for further inhibitor screening, and as a starting point for inhibitor development.

Twenty-nine fluorinated corroles were prepared, spectroscopically characterized, and studied for their antiviral activity against human cytomegalovirus infection. Six corroles were also fully characterized by X-ray crystallography giving insights on their geometrical features. The halogenated corroles reported herein exhibit significantly improved antiviral activity over their non-halogenated counterparts and over nitro-corrole analogs previously reported. Full activity of thirteen A 3 -corroles is achieved with four fluorine atoms present on the meso -phenyl ring reaching a selectivity index above 300. The maximum activity is achieved for A 2 B-corroles with selectivity indexes above 400. We thus demonstrate that the fluorocorrole is a highly potent platform to synthesize a new generation of anti hCMV molecules.

Infections that stem from bacterial biofilms are difficult to eradicate. Within a biofilm state, bacteria are upwards of 1000-fold more resistant to conventional antibiotics, necessitating the development of alternative approaches to treat biofilm-based infections. One such approach is the development of small molecule adjuvants that can inhibit/disrupt bacterial biofilms. When such molecules are paired with conventional antibiotics, these dual treatments present a combination approach to eradicate biofilm-based infections. Previously, we have demonstrated that small molecules containing either a 2-amino pyrimidine (2-AP) or a 2-aminoimidazole (2-AI) heterocycle are potent anti-biofilm agents. Herein, we now report a scaffold hopping strategy to generate new aryl 2-AP analogs that inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA). These molecules also suppress colistin resistance in colistin resistant Klebsiella pneumoniae , lowering the minimum inhibitory concentration (MIC) by 32-fold.

Of the manifold concepts in drug discovery and design, covalent drugs have re-emerged as one of the most promising over the past 20-or so years. All such drugs harness the ability of a covalent bond to drive an interaction between a target biomolecule, typically a protein, and a small molecule. Formation of a covalent bond necessarily prolongs target engagement, opening avenues to targeting shallower binding sites, protein complexes, and other difficult to drug manifolds, amongst other virtues. This opinion piece discusses frameworks around which to develop covalent drugs. Our argument, based on results from our research program on natural electrophile signaling, is that targeting specific residues innately involved in native signaling programs are ideally poised to be targeted by covalent drugs. We outline ways to identify electrophile-sensing residues, and discuss how studying ramifications of innate signaling by endogenous molecules can provide a means to predict drug mechanism and function and assess on- versus off-target behaviors.

The lifetime of a binary drug–target complex is increasingly acknowledged as an important parameter for drug efficacy and safety. With a better understanding of binding kinetics and better knowledge about kinetic parameter optimization, intentionally induced prolongation of the drug–target residence time through structural changes of the ligand could become feasible. In this study we assembled datasets from 21 publications and the K4DD (Kinetic for Drug Discovery) database to conduct large scale data analysis. This resulted in 3812 small molecules annotated to 78 different targets from five protein classes (GPCRs: 273, kinases: 3238, other enzymes: 240, HSPs: 160, ion channels: 45). Performing matched molecular pair (MMP) analysis to further investigate the structure–kinetic relationship (SKR) in this data collection allowed us to identify a fundamental contribution of a ligand's polarity to its association rate, and in selected cases, also to its dissociation rate. However, we furthermore observed that the destabilization of the transition state introduced by increased polarity is often accompanied by simultaneous destabilization of the ground state resulting in an unaffected or even worsened residence time. Supported by a set of case studies, we provide concepts on how to alter ligands in ways to trigger on-rates, off-rates, or both.

The most widely used method for the control of the Aedes aegypti mosquito population is the chemical control method. It represents a time- and cost-effective way to curb several diseases ( e.g. dengue, Zika, chikungunya, yellow fever) through vector control. For this reason, the discovery of new compounds with a distinct mode of action from the available ones is essential in order to minimize the rise of insecticide resistance. Detoxification enzymes are an attractive target for the discovery of new insecticides. The kynurenine pathway is an important metabolic pathway, and it leads to the chemically stable xanthurenic acid, biosynthesized from 3-hydroxykynurenine, a precursor of reactive oxygen and nitrogen species, by the enzyme 3-hydroxykynurenine transaminase (HKT). Previously, we have reported the effectiveness of 1,2,4-oxadiazole derivatives acting as larvicides for A. aegypti and AeHKT inhibitors from in vitro and in silico studies. Here, we report the synthesis of new sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] propanoates and the cognate HKT-inhibitory activity. These new derivatives act as competitive inhibitors with IC 50 values in the range of 42 to 339 μM. We further performed molecular docking simulations and QSAR analysis for the previously synthesized sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanoates reported earlier by our group and the data produced herein. Most of the 1,2,4-oxadiazole derivatives, including the canonical compounds for both series, showed a similar binding mode with HKT. The binding occurs similarly to the co-crystallized inhibitor via anchoring to Arg 356 and positioning of the aromatic ring and its substituents outwards at the entry of the active site. QSAR analysis was performed in search of more than 770 molecular descriptors to establish a relationship between the lowest energy conformations and the IC 50 values. The five best descriptors were selected to create and validate the model, which exhibited parameters that attested to its robustness and predictability. In summary, we observed that compounds with a para substitution and heavier groups ( i.e. CF 3 and NO 2 substituents) had an enhanced HKT-inhibition profile. These compounds comprise a series described as AeHKT inhibitors via enzymatic inhibition experiments, opening the way to further the development of new substances with higher potency against HKT from Aedes aegypti .

NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2′-3′-cyclic phosphates 5′ to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based ‘(2 S ,3 S )-3-amino-1-(4-(4-( tert -butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol’ ( IV ) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays . This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IV was not toxic to the cell lines up to a 50 μM concentration and exhibited IC 50s of 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.

There is an urgent need for new therapies to overcome antimicrobial resistance (AMR) especially against Gram-negative bacilli (GNB). Multicomponent therapy combining antibiotics with enhancer molecules known as adjuvants is an emerging strategy to combat AMR. We have previously reported tobramycin-based adjuvants which are able to potentiate various antibiotics. In order to expand the repertoire of tobramycin hybrid adjuvants, a new hybrid containing niclosamide, an FDA approved anthelmintic which has recently demonstrated a variety of interesting biological effects, was synthesized. It was found that this conjugate can potentiate several antibiotics against multidrug-resistant GNB, including the recently approved siderophore cephalosporin cefiderocol. 8 μg ml ?1 of the niclosamide–tobramycin hybrid in combination therapy against a pandrug-resistant strain of P. aeruginosa was able to lower the cefiderocol MIC 32-fold, from 8 μg ml ?1 to 0.25 μg ml ?1 in iron-rich media where siderophore uptake is reduced. These results indicate that a niclosamide–tobramycin hybrid adjuvant can serve to potentiate a newly approved antibiotic.

The development of multidrug resistance in the malarial parasite has sabotaged majority of the eradication efforts by restraining the inhibition profile of first line as well as second line antimalarial drugs, thus necessitating the development of novel pharmaceutics constructed on appropriate scaffolds with superior potency against the drug-resistant and drug-susceptible Plasmodium parasite. Over the past decades, the infectious malarial parasite has developed resistance against most of the contemporary therapeutics, thus necessitating the rational development of novel approaches principally focused on MDR malaria. This review presents an epigrammatic collation of the epidemiology and the contemporary antimalarial therapeutics based on the ‘ azole ’ motif.