Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor.

A novel Rh-catalyzed one-pot homo-coupling reaction of aryl Grignard reagents was achieved. The reaction with bromobenzenes having an electron-donating group or a halogen substituent gave the corresponding homo-coupling products in good yields, although the reaction using heterocyclic or aliphatic bromides scarcely proceeded. A Rh(III)-bis(aryl) complex, which might be formed from RhCl(PPh3)3 and the aryl Grignard reagents, plays an important role in giving the homo-coupling products in this reaction. Furthermore, we applied the reaction to the synthesis of a novel inhibitor for integrins which is critical for several diseases.

Decarboxylative Aldol Reaction of α,α-Difluoro-ß-keto Esters: Easy Access to Difluoroenolate.

Yb(OTf)3 promoted the Krapcho decarboxylation of 2,2-difluoro-3-oxopropanoate, and a subsequent aldol reaction was achieved. This process is the first example of generating difluoroenolates through a decarboxylation-type process, and a large number of carbonyl compounds are applicable to the aldol reaction. The protocol is a complete one-pot reaction that uses the bench-stable and nonhygroscopic 2,2-difluoro-3-oxopropanoate to generate the difluoroenolate. This strategy has been applied for the synthesis of CF2-containing bioactive GABAB agonists, contributing to drug design.

Pentafluorosulfanyl-substituted biaryl derivatives as MATE-type transporter inhibitors targeting drug-resistant bacteria.

Multidrug and toxin extrusion (MATE) inhibitors improve the antimicrobial susceptibility of drug-resistant bacteria by preventing the efflux of administered antibiotics. In this study, we optimized the chemical structure of a previously identified bacterial-selective MATE inhibitor 1 (EC50 > 30 µM) to improve its activity further. Compound 1 was divided into three fragments (aromatic part, linker part, and guanidine part), and each part was individually optimized. Compound 31 (EC50 = 1.8 µM), a novel pentafluorosulfanyl-containing molecule synthesized following optimized parts, showed antimicrobial activity against MATE-expressing strains at concentrations lower than conventional inhibitor 1 when co-administrated with norfloxacin. Furthermore, 31 was not cytotoxic at effective concentrations. This suggests that compound 31 can be a promising candidate for combating bacterial infections, particularly those resistant to conventional antibiotics by MATE expression.

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks.

In recent years, hydrofluorocarbon compounds such as chlorofluorocarbons, hydrochlorofluorocarbons, and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) have been used as fluorine-containing building blocks to construct functional fluorine-containing compounds, e. g., polymers, liquid crystals, and medicines. Hydrofluorocarbons promote the formation of reactive fluoroalkyl or fluoroalkenyl species via anionic or radical processes, and these species can act as nucleophiles or electrophiles depending on the reaction conditions. Progress in fluorine chemistry using hydrofluorocarbons in the last 30 years is described in this review and diverse reactions are discussed, including the fluoroalkyl/alkenyl products and proposed mechanisms involved.

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone.

A rhodium-catalyzed intramolecular reductive aldol-type cyclization is described to give ß-hydroxylactones with high diastereoselectivities. The stereoselectivity of this cyclization is highly solvent dependent and can give syn- or anti-ß-hydroxylactones with high diastereoselectivity. This methodology was also applied to the synthesis of a chiral necic acid lactone which is a structural component of the pyrrolizidine alkaloid monocrotaline.

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane).

A series of aryl fluoroalkenyl ethers that contain chlorine and bromine as well as fluorine atoms were prepared in moderate to good yields via the reactions of phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) in the presence of KOH. This simple reaction enabled the construction of highly halogenated compounds with the potential for further functionalization. The reaction involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH.

Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections.

Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.

Discovery of benzyloxyphenyl- and phenethylphenyl-imidazole derivatives as a new class of ante-drug type boosters.

Although cytochrome P450 3A4 (CYP3A4) inhibitors are used as boosters to increase drug absorption, the inhibition of CYP3A4 activity may affect the metabolism of other co-administered drugs. Therefore, we screened for and developed a new class of boosters to improve the oral availability of drugs. We identified benzyloxyphenyl imidazole and phenethylphenyl imidazole derivatives as new types of CYP3A4 inhibitors. Among the compounds synthesized, an ester 5c was found to inhibit CYP activity and the compound 5c was gradually converted to an inactive metabolite 5d under physiological conditions, indicating that the ester 5c may represent a novel ante-drug type booster.

LCP: Simple Representation of Docking Poses for Machine Learning: A Case Study on Xanthine Oxidase Inhibitors.

In this paper, we propose a simple descriptor called the ligand coordinate profile (LCP) for describing docking poses. The LCP descriptor is generated from the coordinates of the polar hydrogen and heavy atoms of the docked ligand. We hypothesize that the prediction of binding poses can be enhanced through the combination of machine learning methods with the LCP descriptor. Two docking programs were used to predict ligand docking against xanthine oxidase. Four machine learning methods-k-nearest neighbors, random forest, support vector machine, and LightGBM-were used to determine whether machine learning-based models could be used to accurately identify the correct binding poses. Regardless of the machine learning method employed, the LCP descriptor demonstrated improved performance compared to the existing descriptor. The results of the leave-one-pdb-out approach revealed that the influence of the pose descriptor was also significant, as demonstrated through cross-validation. When evaluated using top-N metrics, the machine learning models were generally more effective than the docking programs. In addition, the LCP-based models outperformed those based on the existing descriptor. The results obtained in this study suggest that our proposed binding pose descriptor is effective for improving the docking accuracy of xanthine oxidase inhibitors.

Importance of the Azole Moiety of Cimetidine Derivatives for the Inhibition of Human Multidrug and Toxin Extrusion Transporter 1 (hMATE1).

Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.

Identification and Synthesis of DDI-6, a Quinolinol Analog Capable of Activating Both Caenorhabditis elegans and Mouse Spermatozoa.

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

N-Acyltriazinedione; a Novel Acylating Reagent Synthesized from a Triazinone-Type Condensing Reagent.

In this paper, we report the synthesis of N-acyltriazinedione via the unexpected O-N acyl rearrangement of acyloxytriazinone and its utility as an acylating reagent. N-Acyltriazinedione can be isolated by silica gel column chromatography and reacts with amines in the absence of any base to give the corresponding amides in good yields.

Effect of Learning Dataset for Identification of Active Molecules: A Case Study of Integrin αIIbß3 Inhibitors.

Efficient in silico approaches are needed to identify strong integrin αIIbß3 inhibitors through a small number of measurements. To address the challenge, we investigated the effect of learning dataset on the classification performance of machine learning models focusing on weak and inactive compounds. The structure and activity information of the compounds were obtained from ChEMBL, and pCHEMBL values were used to classify them as active, inactive, or weak. Datasets with various imbalance levels from active:inactive=1 : 1 to 1 : 1000 were used for the machine learning. The prediction scores of the weak samples were found to lie between the predictive values of active and inactive compounds. In addition, another dataset that consists of 149 actives and 6.9 million inactives was screened; the results indicated that the number of positive predictions decreased for models trained with a higher number of inactives. Although there is a trade-off between false positives and false negatives, for determination of compounds with strong activity using a reduced number of measurements, it is better to use a large number of inactives for learning and identifying compounds that score higher than the weak samples.

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane.

An efficient and convenient method for the synthesis of structurally unique and highly functionalized aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers has been developed. This approach exhibits a broad reaction scope, a simple operation and without the need of any expensive transition-metal catalyst, highly toxic or corrosive reagents. Notably, we demonstrate the potential utility of halothane for the synthesis of aryl gem-difluoroalkyl ethers containing the bromochloromethyl group.

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles.

Fluorescent molecules based on a fluorinated isoxazole scaffold were synthesized and investigated for their photochemical properties. The introduction of a fluorine substituent into 3,5-diarylisoxazoles led to an increase of fluorescence intensity and exhibited a redshift in the emission intensity. α-Fluorinated boron ketoiminates (F-BKIs) were also synthesized via a ring-opening reaction of 4-fluoroisoxazoles and exhibited highly fluorescent luminescence and aggregation-induced emission (AIE), showing promise as a new fluorophore.

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkenes Using AgCF3.

A mild and convenient reaction for oxidative trifluoromethylation of terminal alkenes was developed using in situ generated AgCF3 in the presence of a copper catalyst. The reaction proceeded under an air atmosphere to afford trifluoromethylated allylic compounds in moderate to good yield. This reaction, with no need for highly hygroscopic or corrosive reagents, features not only a simple operation but also various functional group tolerances.

Effect of Structural Descriptors on the Design of Cyclin Dependent Kinase Inhibitors Using Similarity-based Molecular Evolution.

In this study, we evaluated the effect of structural descriptors on the in silico design of bioactive compounds. The authors have proposed a molecular design technique for designing new bioactive compounds. In this approach, known fragments are combined to generate new structures, which are evolved to increase the similarity to a known active compound. We generated the structure of CDK2 inhibitors using four descriptors (three binary fingerprints and a numerical vector) to evaluate the effect of descriptors on the molecular design. Subsequently, the physicochemical properties of the generated compounds were compared and evaluated from a similarity viewpoint. As a result, it was clarified that better structures can be generated by using descriptors consisting of numerical vectors rather than binary fingerprints. Moreover, the compound generated using the numerical vector or a long-bit fingerprint resulted in favorable docking scores. Although binary fingerprints such as MACCS are widely used in this field, this result shows that it is important to use numeric vectors, or at least to use long-bit fingerprints, to design drug-like CDK2 inhibitors by the similarity-based structure generation.

Synthesis of Small Fluorescent Molecules and Evaluation of Photophysical Properties.

A series of aniline-based fluorophores were newly synthesized. To increase their fluorescence quantum yields, it was particularly important to substitute 3,3,3-trifluoroprop-1-enyl (TFPE) groups next to the amino group to benefit from an extended π-electron delocalization. Among these, 5-CN-2-TFPE-aniline was found to behave as an excellent fluorophore with a reasonable fluorescence quantum yield of 0.89 even in aqueous solution. l-Alanine peptide, a nonfluorescent analogue of 5-CN-2-TFPE-aniline, was synthesized and successfully employed as an enzyme probe to detect aminopeptidase N activity.

Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions.

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were -13.80 kcal/mol for COX-1 and -18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.

Development of Triazine-Based Benzylating Reagents Possessing t-Butyl Group on the Triazine Core: Thermally Controllable Reagents for the Initiation of Reaction.

Benzylating reagents, 4-(4,6-di-t-butyl-1,3,5-triazin-2-yl)-4-benzylmorpholinium triflate, and related derivatives have been developed. The reagents release benzyl triflate as a benzyl cation equivalent upon heating the solution to 40°C under neutral conditions. The O-benzylation of alcohols using a stoichiometric amount of these reagents afforded corresponding benzyl ethers in good to high yields. This was due to the presence of a bulky t-butyl group on the triazine ring of these reagents that prevents the consumption of benzyl triflate via a side reaction with a morpholinotriazine derivative.