The Death of the Strategy of Classical Chiral Switches Is an Exaggeration.

The strategy of classical chiral switches of drugs is still alive, contrary to a 2024 Perspective on approved chiral drugs claiming its death. Surveys of approved chiral-switch and racemic drugs should be based on reports of global regulatory authorities, not just FDA and EMA, which revealed overlooked chiral switches and racemates. The approved antihypertensive racemate nebivolol indicates the synergy between its enantiomers, highlighting the advocacy of developing racemic drugs.

Correction to "The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy".

[This corrects the article DOI: 10.1021/acsptsci.2c00151.

Chiral Switches of Tramadol Hydrochloride, a Potential Psychedelic Drug-Past and Future.

The chiral opioid analgesic tramadol was patented (1962) as a - and -racemates mixture. A first chiral switch led to the (±)--(1,2) racemate, patented and approved as Tramal (1980), preferred over the (+)--(1,2)-enantiomer. Consecutive chiral switches of (±)--tramadol to (+)--(1,2)-tramadol/salts were patented.

Comment on "Asymmetric Bistricyclic Aromatic Enes".

This Correspondence argues against the use of the adjectives "symmetrical" and "asymmetric" in the recent publication entitled "Fluorenylidene-Cyclopentadithiophene Based Asymmetric Bistricyclic Aromatic Ene Compounds: Synthesis and Substituents Effects", by Beibei Xiao, Yongrui Yang, Shengnan Chen, Ye Zou, Xing Chen, Kanglei Liu, Nan Wang, Yali Qiao, and Xiaodong Yin (Chem. Eur. J.

Chiral distinction between hydroxychloroquine enantiomers in binding to angiotensin-converting enzyme 2, the forward receptor of SARS-CoV-2.

Soon after the outset of the Coronavirus Disease 2019 (COVID-19) pandemic (March-April 2020), formulations of the old antimalarial racemic drug hydroxychloroquine (HCQ) sulfate were authorized by the U.S. Food and Drug Administration (FDA) for emergency treatment of hospitalized patients with COVID-19.

The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy.

Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked.

Distinction between 2'- and 3'-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration.

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging.

In Defense of Secondary Pharmaceutical Patents in Drug Discovery and Development.

"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary pharmaceuticals. This Viewpoint's focus is the defense of the vulnerable strategy of secondary pharmaceutical patents (SPPs). Typical claims thereof are new medical uses, dosage, selection, and enatiomer patents.

Regioselectivity in the Controversial Scholl Reaction of 1-Benzoylpyrene: Formation of a Five-Member Ring Is Not Unexpected.

Intramolecular Scholl reaction of 1-benzoylpyrene (1) gave 8H-dibenzo[def,qr]chrysen-8-one (2) and 11H-indeno[2,1-a]pyren-11-one (3) in a 1:2 ratio. The structures of 2 and 3 were determined, using H NMR, C NMR, and IR spectroscopies. A DFT B3LYP/6-311G(d,p) study of the reaction's arenium-cation mechanism of (E)-1 and (Z)-1 giving 2 and 3, respectively, indicated the reaction's regioselectivity and kinetic control.

Classroom Enters the Courtroom: Stereochemistry of SN1 and SN2 Reactions in Enantiomer Patent Litigations of the Antidepressant Escitalopram.

The role of elementary stereochemistry is illustrated in the patent litigations of the blockbuster antidepressant drug escitalopram oxalate. An undergraduate student of organic chemistry would recognize the stereochemical courses of the intramolecular SN 2 and SN 1 reactions of the single-enantiomer (S)-diol intermediate in the synthesis of the blockbuster antidepressant drug escitalopram oxalate: retention of configuration of the chiral carbon atom under basic conditions and racemization under acidic conditions, respectively. He/she, in searching for a stereoselective ring-closure reaction of the enantiomeric diol, will think of an SN 2 reaction in a basic medium.

Heteromerous Bistricyclic Aromatic Enes: Dynamic Stereochemistry of Xanthylidene-Anthrones.

The heteromerous bistricyclic aromatic ene (BAE) 2,2'-dimethyl-10-(9H-xanthylidene)-9(10H)-anthrone (DMXA) was synthesized by a condensation of 10,10-dichloro-2-methylxanthene with 2-methylanthrone. X-ray crystallography of (E)-DMXA and xanthylidene-anthrone (XA) indicated that the molecules adopt anti-folded conformations with folding dihedral angles of 44°/44° and 39°/41°, respectively. The crystal structure of anti-folded (E)-DMXA does not indicate any xanthenylium-anthracenolate push-pull effect.

"New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity.

This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations.

Stereochemistry of bistricyclic aromatic enes and related polycyclic systems.

Bistricyclic aromatic enes (BAEs) and related polycyclic systems are a class of molecular materials that display a rich variety of conformations, dynamic stereochemistry and switchable chirality, color, and spectroscopic properties. This is due to the a subtle interplay of the inherent preference for planarity of aromatic systems and the competing necessity of non-planarity due to intramolecular overcrowding in the fjord regions built into the general molecular structure of BAEs. The conformational, dynamic, and spectroscopic properties may be designed and fine-tuned, e.

Single enantiomer versus racemate: chiral distinction in the proton pump inhibitors omeprazole and esomeprazole.

Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral-switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6-311G(d,p), the 6-methoxy∙∙∙6-methoxy and 5-methoxy∙∙∙5-methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG(298,(RS-SS))) between the cyclic C2-(S,S)- and Ci-(R,S)-dimers with two intermolecular hydrogen bonds are 3.

Racemization of the gastrointestinal antisecretory chiral drug esomeprazole magnesium via the pyramidal inversion mechanism: A theoretical study.

The pyramidal inversion mechanisms of the 6-methoxy and the 5-methoxy tautomers of (S)-omeprazole were studied, employing ab initio and DFT methods. The conformational space of the model molecule (S)-2-[(3-methyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole was calculated, with respect to rotations around single bonds, at the B3LYP/6-311G(d,p) level. All of the resulting conformations were used as starting points for full optimizations of (S)-omeprazole, at B3LYP/6-31G(d), B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-311G(2df,2pd), MP2/6-31G(d), and MP2/6-311G(d,p) levels.

The strategy of enantiomer patents of drugs.

Enantiomer patents (ENPTs), constituents of chiral switches, claim single enantiomers of chiral drugs previously claimed as racemates. In this article, the strategy of ENPTs and recent court decisions and trends in case law worldwide are highlighted. ENPTs are challenged frequently (e.

Electrostatic chiral distinction: tetrahedral model dimers.

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four-point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles.

Theoretical notions of aromaticity and antiaromaticity: phenalenyl ions versus fluorenyl ions.

The dications 6, 7, and 8 and dianions 9, 10, and 11 of the bistricyclic aromatic enes bifluorenylidene (1), 1,1'-biphenalenylidene (2), and 9-(9H-fluoren-9-ylidene)-1H-phenalene (4), as well as monocations 12a and 13a and monoanions 14a and 15a of phenalene (3) and fluorene (5), were subjected to a systematic DFT and ab initio study. B3LYP and MP2 methods were employed to estimate the relative aromaticity/antiaromaticity of these ions, using energetic, magnetic, and structural criteria. The couplings of monoions 12a-15a to give the respective diions 6-11 result in a similar destabilization in both the fluorene and phenalene series.

Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: a theoretical study.

The pyramidal inversion mechanism of simple sulfoxides was studied, employing ab initio and DFT methods. The convergence of the geometrical and energetic parameters of H2SO and DMSO with respect to the Hamiltonian and basis set was analyzed in order to determine a computational level suitable for methyl phenyl sulfoxide (3), methyl 4-cyanophenyl sulfoxide (4), diphenyl sulfoxide (5), 4,4'-dicyanodiphenyl sulfoxide (6), benzyl methyl sulfoxide (7) and benzyl phenyl sulfoxide (8). The DFT B3LYP/6-311G(d,p) level was chosen for further calculations of larger sulfoxides.

Polymorphism versus thermochromism: interrelation of color and conformation in overcrowded bistricyclic aromatic enes.

The nature of the thermochromic form of overcrowded bistricyclic aromatic enes (BAEs) has been controversial for a century. We report the single-crystal X-ray structure analysis of the deep-purple and yellow polymorphs of 9-(2,7-dimethyl-9H-fluoren-9-ylidene)-9H-xanthene (11), which revealed the molecules in a twisted and a folded conformation, respectively. Therefore, the deeply colored thermochromic form B of BAEs is identified as having a twisted conformation and the ambient-temperature form A as having a folded conformation.

Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: stereochemistry and tautomerism.

A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P).

Two contact-point chiral distinction: model CHFClBr dimers.

Dimers of the simple chiral molecule CHFClBr have been studied using a variety of computational approaches, including HF, MP2, and DFT B3LYP and the 6-31G*, 6-31++G**, and 6-311++G** basis sets. Both heterochiral and homochiral dimers were studied to allow analysis of the chiral distinction in these systems. The dimers were arranged in edge-to-edge orientations with assorted combinations of two contact-points ("2:2e") between the dimers.