Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates

The discovery of novel drugs against animal parasites is in high demand due to drug‐resistance problems encountered around the world. Herein, the synthesis and characterization of 27 organic and organometallic derivatives of the recently launched nematocidal drug monepantel (Zolvix^®) are described. The compounds were isolated as racemates and were characterized by ¹H, ¹³C, and ¹⁹F NMR spectroscopy, mass spectrometry, and IR spectroscopy, and their purity was verified by microanalysis. The molecular structures of nine compounds were confirmed by X‐ray crystallography. The anthelmintic activity of the newly designed analogues was evaluated in vitro against the economically important parasites Haemonchus contortus and Trichostrongylus colubriformis. Moderate nematocidal activity was observed for nine of the 27 compounds. Three compounds were confirmed as potentiators of a known monepantel target, the ACR‐23 ion channel. Production of reactive oxygen species may confer secondary activity to the organometallic analogues. Two compounds, namely, an organic precursor ( 3 a ) and a cymantrene analogue ( 9 a ), showed activities against microfilariae of Dirofilaria immitis in the low microgram per milliliter range.     

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis**

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH₂-OXA), ruthenocene-containing (Rc-CH₂-OXA) and benzene-containing (Ph-CH₂-OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.     

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

Viral infections pose a persistent threat to human health. The relentless epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health problem, with millions of infections and fatalities so far. Traditional approaches such as random screening and optimization of lead compounds by organic synthesis have become extremely resource- and time-consuming. Various modern innovative methods or integrated paradigms are now being applied to drug discovery for significant resistance in order to simplify the drug process. This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting chimera (RIBOTAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system. This article is dedicated to Prof. Dr. Erik De Clercq, an internationally renowned expert in the antiviral drug research field, on the occasion of his 80th anniversary.     

Raman Spectroscopic Imaging for the Real‐Time Detection of Chemical Changes Associated with Docetaxel Exposure

There is an urgent need for methods allowing for a fast, non‐invasive, sensitive and selective monitoring of the effectiveness of anticancer drugs during the course of a chemotherapeutic treatment of cancer patients. The possibility of predicting and controlling the efficiency of chemotherapeutic agents for every patient individually enables a personalized therapy with largely improved success rates. The results presented herein demonstrate that Raman microspectroscopy is perfectly suited to monitor the impact of chemotherapeutic agents on living cells. The influence of the clinically well‐established chemotherapeutic docetaxel on both the morphology and also biochemistry of living colon cancer cells (HT‐29) has been studied by means of Raman spectroscopy in combination with modern chemometric approaches. The work presented paves the way for establishing Raman spectroscopy as a monitoring tool of the effectiveness of a chemotherapy treatment and can therefore be seen as a step towards personalized therapy.     

Fluorine-containing drugs approved by the FDA in 2019

Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed.Therapeutic areas include schizophrenia,migraine,multiple sclerosis,insomnia,rheumatoid arthritis,anti-tuberculosis,breast cancer,lymphoma kinase inhibitor,serotonin receptor antagonist.New pharmaceuticals feature four examples of aromatic fluorine,three aromatic CF₃ group,three aliphatic CF₃ and one compound with aromatic CF₃O group.F...     

Novel Procedure for the Coupling of Sterically Hindered Electron-Deficient Anilines to the 6-Position of the Purine Core

Sterically hindered electron-deficient anilines are coupled to the 6-position of the purine core only when activated as their corresponding TFA-amide. The free anilines did not react under all conditions tested. After aqueous work-up, the TFA-group is lost.

This procedure provides a new tool in the construction of purines functionalized with a sterically hindered electron-deficient aniline in the 6-position.      

Antiviral Peptides (AVPs) of Marine Origin as Propitious Therapeutic Drug Candidates for the Treatment of Human Viruses

The marine environment presents a favorable avenue for potential therapeutic agents as a reservoir of new bioactive natural products. Due to their numerous potential pharmacological effects, marine-derived natural products—particularly marine peptides—have gained considerable attention. These peptides have shown a broad spectrum of biological functions, such as antimicrobial, antiviral, cytotoxic, immunomodulatory, and analgesic effects. The emergence of new virus strains and viral resistance leads to continuing efforts to develop more effective antiviral drugs. Interestingly, antimicrobial peptides (AMPs) that possess antiviral properties and are alternatively regarded as antiviral peptides (AVPs) demonstrate vast potential as alternative peptide-based drug candidates available for viral infection treatments. Hence, AVPs obtained from various marine organisms have been evaluated. This brief review features recent updates of marine-derived AVPs from 2011 to 2021. Moreover, the biosynthesis of this class of compounds and their possible mechanisms of action are also discussed. Selected peptides from various marine organisms possessing antiviral activities against important human viruses—such as human immunodeficiency viruses, herpes simplex viruses, influenza viruses, hepatitis C virus, and coronaviruses—are highlighted herein.     

Heterocycle‐linked Phenylbenzyl Amides as Novel TRPV1 Antagonists and Their TRPV1 Binding Modes: Constraint‐Induced Enhancement of In Vitro and In Vivo Activities

A series of heterocycle‐linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan‐linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model.     

Interaction of Metal Complexes with G‐Quadruplex DNA

Guanine‐rich sequences of DNA can assemble into tetrastranded structures known as G‐quadruplexes. It has been suggested that these secondary DNA structures could be involved in the regulation of several key biological processes. In the human genome, guanine‐rich sequences with the potential to form G‐quadruplexes exist in the telomere as well as in promoter regions of certain oncogenes. The identification of these sequences as novel targets for the development of anticancer drugs has sparked great interest in the design of molecules that can interact with quadruplex DNA. While most reported quadruplex DNA binders are based on purely organic templates, numerous metal complexes have more recently been shown to interact effectively with this DNA secondary structure. This Review provides an overview of the important roles that metal complexes can play as quadruplex DNA binding molecules, highlighting the unique properties metals can confer to these molecules.     

A Machine‐Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor‐1

Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1 ), a neurotensin receptor‐1 antagonist, with its machine‐assisted flow chemistry alternative. By using these enabling tools, combined with solid‐supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.     

Total Synthesis of (18S)‐ and (18R)‐Homolargazole by Rhodium‐Catalyzed Hydrocarboxylation

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium‐catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)‐ and (18R)‐stereoisomers in high stereoselectivity under ligand control.