Medicinal Chemistry Research Articles

Enhanced Sampling in Molecular Dynamics Simulations: How Many MD Snapshots can be Needed to Reproduce the Biological Behavior?

Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

Gold-catalyzed Reactions of Substituted 1,5-diynes: Recent Advances and their Chemistry

Abstract: Diynes are identified as exceptionally potent and superior substrates in gold-catalyzed organic transformations. Gold (I) and gold (III) complexes exhibit unique activity towards diynes, encouraging the nucleophilic addition of different functional groups both inter and intra- molecularly. In this review, particularly, we focused on recent advances in gold-catalyzed reactions of 1,5-diynes along with their mechanistic aspects. These reactions are interesting for constructing molecular complexity, medicinal chemistry, and material science.

Recent Progress on Synthesis of Functionalized 1,5-Disubstituted Triazoles.

Immediately after the invention of 'Click Chemistry' in 2002, the regioselective 1,2,3- triazole scaffolds resulted from respective organic azides and terminal alkynes under Cu(I) catalysis have been well recognized as the functional heterocyclic core at the centre of modern organic chemistry, medicinal chemistry, and material sciences. This CuAAC reaction has several notable features including excellent regioselectivity, high-to-excellent yields, easy to execute, short reaction time, modular in nature, mild condition, readily available starting materials, etc. Moreover, the resulting regioselective triazoles can serve as amide bond isosteres, a privileged functional group in drug discovery and development. More than hundreds of reviews had been devoted to the 'Click Chemistry' in special reference to 1,4-disubstituted triazoles, while only little efforts were made for an opposite regioisomer i.e., 1,5-disubstituted triazole. Herein, we have presented various classical approaches for an expeditious synthesis of a wide range of biologically relevant 1,5- disubstituted 1,2,3-triazole analogues. The syntheses of such a class of diversly functionalized triazoles have emerged as a crucial investigation in the domain of chemistry and biology. This tutorial review covers the literature assessment on the development of various synthetic protocols for the functionalized 1,5-disubstituted triazoles reported during the last 12 years.

Advances in Synthesis of Indazole Variants: A Comprehensive Review of Transition Metal, Acid/Base and Green Chemistry-based Catalytic Approaches

Background:: Indazole is a heterocyclic motif widely used in medicinal chemistry due to its positive photophysical properties. The development of new methods for synthesizing the indazole scaffold is of great importance in drug discovery. Methods:: This study presents a detailed review of current advances in indazole synthesis, focusing on catalyst-based and green chemistry approaches. The analysis is classified based on acid-base and transition-metal catalysts and green chemistry methods. Catalyst-based advances have given a new impetus to the synthesis of this effective pharmacophore. Results:: The extensive literature on indazole synthesis demonstrates the notable progress achieved through catalyst-based approaches. These methods have enabled researchers to create a wide range of indazole derivatives and analogs, facilitating their application in pharmaceutical products and organic molecules. The use of acid-base and transition-metal catalysts has been particularly effective in enhancing the efficiency and selectivity of indazole synthesis. Conclusion:: Indazoles and their variants are widely used in pharmaceutical products and organic molecules. The recent literature indicates that catalyst-based approaches have resulted in significant advancements in indazole synthesis. This review may be useful for researchers in medicinal chemistry, content chemistry, and agrochemistry.

Synthesis and In Silico Studies of Quinazolinones as PARP-1 Inhibitors.

Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer. PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities. In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software. Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates. All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

Synthesis of Methyl N-phenylcarbamate Derivatives by Xphos Pd G2 Catalyzed Intermolecular Amidation Reaction

Abstract: The utilization of palladium catalysts in cross-coupling reactions has emerged as a highly promising method for the facile formation of aryl C-N bonds, operating under mild conditions. In this study, we present an efficient approach for the synthesis of methyl N-phenyl carbamate derivatives through the intermolecular amidation of aryl chlorides, catalyzed by Xphos Pd G2. The developed protocol has demonstrated remarkable efficacy, offering several advantages. Notably, the intermolecular amidation reaction exhibited good chemoselectivity, allowing for the precise targeting of desired C-N bond formations while maintaining the integrity of other functional groups. Additionally, this methodology showcases exceptional functional group compatibility, accommodating a diverse array of moieties, including sensitive groups that are traditionally challenging to handle. The Xphos Pd G2 catalyst has proven to be instrumental in orchestrating this transformation, exhibiting high catalytic activity and selectivity. Furthermore, this protocol stands out for its operational simplicity, making it a practical choice for synthetic chemists seeking a straightforward and reliable route to access methyl N-phenyl carbamate derivatives. Overall, this study not only expands the synthetic toolbox for C-N bond formations, but also underscores the significance of palladium-catalyzed methodologies in modern organic synthesis. The reported findings hold substantial promise for applications in medicinal chemistry and material science, where the facile construction of aryl C-N bonds is of paramount importance.

One-pot Synthesis of Condensed Azepines

Abstract: Azepine is a privileged nitrogen-containing ring that has been found to display a wide range of biological activities. Azepine is a valuable skeleton in designing novel compounds in medicinal chemistry due to its interesting chemical and biological properties. The study on the synthesis of this ring system engenders a fascinating area of research owing to its potential to form an active pharmacophore for De Novo exploration. In this study, conventional and domino results were compared to access the diverse set of azepines in high yield. The domino approach has revolutionized the way through which the previously impossible yet significant transformations could be conceptualized, allowing the construction of difficult materials in one step. The aim of the present mini-review is to highlight the importance of the one-pot domino reaction for the synthesis of condensed azepines. This review also presents research on this subject from the past two decades.

Advances in drug design and therapeutic potential of selective or multitarget 5-HT1A receptor ligands.

5-HT1A receptor (5-HT1A-R) is a serotoninergic G-protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5-HT-R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure-activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5-HT1A-R selective/preferential ligands; (ii) identification of 5-HT1A-R biased agonists, differentiating pre- versus post-synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well-defined poly-pharmacological profiles targeting 5-HT1A-R along with other serotonin receptors, serotonin transporter (SERT), D2-like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5-HT1A-R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017-2023) have been discussed. The development of chemical and pharmacological 5-HT1A-R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5-HT1A-R and the therapeutic potential of ligands targeting this receptor have been considered.

Multigram Synthesis of 4,4-Disubstituted 3-Oxopyrrolidones: Efficient Starting Materials for Diverse 3-Functionalized Pyrrolidones

AbstractThe practical, rapid development of chemical leads for drug discovery depends strongly on scalable building block synthesis procedures. N-Heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. The synthesis of 4,4-disubstituted 3-oxopyrrolidones was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones, and 3,3′-difluoropyrrolidines. These compounds can be functionalized with conformationally flexible spirocyclic substituents. We developed a multigram procedure to access 4,4-disubstituted 3-oxopyrrolidones from commercially accessible and cost-saving reagents via a short three-step procedure. Here, we report the robust conversion of 3-oxopyrrolidones into 3-aminopyrrolidones, 3,3′-difluoropyrrolidones, and 3-hydroxypyrrolidones, involving a minimal number of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches.

Iodine(III)-Mediated Ring-Contraction Reactions Using Halogenated and Non-halogenated Solvents

AbstractThe transformation of a six-membered ring into the corresponding five-membered product is an important synthetic approach used in medicinal chemistry and industrial technologies. However, the yield of the product obtained through a simple one-step reaction is lower in some reported solvent systems. Here, we present the ring contraction of 1,2-dihydronaphthalene derivatives into the corresponding indanes­ using an environmentally friendly reagent hydroxy(tosyloxy)iodobenzene (HTIB). This transformation is achieved in both non-halogenated and halogenated solvents. We show that the halogenated solvent system not only increased the yield of the anticipated product but also reduced the formation of by-products. This study delivers an important development regarding the effectiveness of hypervalent iodine reagents in halogenated and non-halogenated solvents for ring-contraction reactions.

A novel in vitro high-content imaging assay for the prediction of drug-induced lung toxicity.

The development of inhaled drugs for respiratory diseases is frequently impacted by lung pathology in non-clinical safety studies. To enable design of novel candidate drugs with the right safety profile, predictive in vitro lung toxicity assays are required that can be applied during drug discovery for early hazard identification and mitigation. Here, we describe a novel high-content imaging-based screening assay that allows for quantification of the tight junction protein occludin in A549 cells, as a model for lung epithelial barrier integrity. We assessed a set of compounds with a known lung safety profile, defined by clinical safety or non-clinical in vivo toxicology data, and were able to correctly identify 9 of 10 compounds with a respiratory safety risk and 9 of 9 compounds without a respiratory safety risk (90% sensitivity, 100% specificity). The assay was sensitive at relevant compound concentrations to influence medicinal chemistry optimization programs and, with an accessible cell model in a 96-well plate format, short protocol and application of automated imaging analysis algorithms, this assay can be readily integrated in routine discovery safety screening to identify and mitigate respiratory toxicity early during drug discovery. Interestingly, when we applied physiologically-based pharmacokinetic (PBPK) modelling to predict epithelial lining fluid exposures of the respiratory tract after inhalation, we found a robust correlation between in vitro occludin assay data and lung pathology in vivo, suggesting the assay can inform translational risk assessment for inhaled small molecules.

Stellane at the Forefront: Derivatization and Reactivity Studies of a Promising Saturated Bioisostere of ortho-Substituted Benzenes.

This work highlights stellane's cage stability and derivatization opportunities. A diverse range of building blocks were synthesized using modern synthesis protocols to demonstrate stellane's reactivity and chemical tolerance across different reaction systems, proving its promise as a bioisosteric scaffold. It can be utilized in scaffold-based molecular design and is superior in terms of topological precision compared to existing ortho isosteres, as well as monosubstituted benzene mimetics, holding the potential to become a robust platform for future medicinal chemistry studies.

IKZF2 Degradation: It's Time to Take into Account it When Designing Cereblon-based PROTACs.

Proteolysis-targeting chimera (PROTAC) has become a very important means of protein degradation and a new way of disease treatment. In particular, PROTACs constructed with ligands for E3 ligase cereblon account for more than 90% of the PROTACs currently in clinical research. Notably, CRBN ligands themselves are a class of molecular glue compounds capable of degrading neo-substrate proteins. Compared to the target proteins degradation, the degradation of neo-substrates, especially IKZF2, has not received enough attention. Therefore, this review summarizes the currently published IKZF2 degraders derived from articles and patents, which are conducive to the design of PROTACs with desired IKZF2 degradation from the perspective of medicinal chemistry.

Aptamer-RIBOTAC Strategy Enabling Tumor-Specific Targeted Degradation of MicroRNA for Precise Cancer Therapy.

MicroRNA (miRNA) molecules play crucial roles in a variety of diseases, making miRNA targeting a burgeoning field in medicinal chemistry. Ribonuclease targeting chimeras (RIBOTACs) present a compelling approach for RNA degradation. However, small molecule-based RIBOTAC requires an expensive and time-consuming screening process, and is difficult to directly target miRNA due to its short length lacking secondary structure. Antisense oligonucleotide (ASO)-based RIBOTAC is easy to design but with poor cell permeability. While both of them lack the specificity for tumor targeting. In this study, the first Aptamer-RIBOTAC (ARIBOTAC) chimera is designed based on ASO to achieve precise degradation of miRNA in a tumor cell-specific manner for precise cancer therapy. This chimera exhibits a remarkable ability to specifically identify and enter cancer cells, trigger localized activation of endogenous RNase L, and selectively cleave miRNAs that are complementary to ASO. The efficacy and universality of the ARIBOTAC strategy both in vitro and in vivo by degrading oncogenic miR-210-3p and miR-155-5p are validated. These findings underscore the potential of the ARIBOTAC strategy as a promising avenue for cancer therapy by precisely targeting cancer-associated miRNAs.

Research on the Medicinal Chemistry and Pharmacology of Taxus × media

Research on the Medicinal Chemistry and Pharmacology of Taxus × media

Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis.

Porphyrin atropisomerism, which arises from restricted σ-bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20-tetrakis(o-hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

Sulfinamide Crossover Reaction.

This study unveils a new catalytic crossover reaction of sulfinamides. Leveraging mild acid catalysis, the reaction demonstrates a high tolerance to structural variations, yielding equimolar products across diverse sulfinamide substrates. Notably, small sulfinamide libraries can be selectively oxidized to sulfonamides, providing a new platform for ligand optimization and discovery in medicinal chemistry. This crossover chemotype provides a new tool for high-throughput experimentation in discovery chemistry.

Changes in CpG Methylation of the Vitellogenin 1 Promoter in Adult Male Zebrafish after Exposure to 17α-Ethynylestradiol.

Numerous pharmaceutical and industrial chemicals are classified as endocrine-disrupting chemicals (EDCs) that interfere with hormonal homeostasis, leading to developmental disorders and other pathologies. The synthetic estrogen 17α-ethynylestradiol (EE2) is used in oral contraceptives and other hormone therapies. EE2 and other estrogens are inadvertently introduced into aquatic environments through municipal wastewater and agricultural effluents. Exposure of male fish to estrogens increases expression of the egg yolk precursor protein vitellogenin (Vtg), which is used as a molecular marker of exposure to estrogenic EDCs. The mechanisms behind Vtg induction are not fully known, and we hypothesized that it is regulated via DNA methylation. Adult zebrafish were exposed to either dimethyl sulfoxide or 20 ng/L EE2 for 14 days. Messenger RNA (mRNA) expression and DNA methylation were assessed in male zebrafish livers at 0, 0.25, 0.5, 1, 4, 7, and 14 days of exposure; and those of females were assessed at 13 days (n ≥ 4/group/time point). To test the persistence of any changes, we included a recovery group that received EE2 for 7 days and did not receive any for the following 7 days, in the total 14-day study. Methylation of DNA at the vtg1 promoter was assessed with targeted gene bisulfite sequencing in livers of adult male and female zebrafish. A significant increase in vtg1 mRNA was observed in the EE2-exposed male fish as early as 6 h. Interestingly, DNA methylation changes were observed at 4 days. Decreases in the overall methylation of the vtg1 promoter in exposed males resulted in levels comparable to those in female controls, suggesting feminization. Importantly, DNA methylation levels in males remained significantly impacted after 7 days post-EE2 removal, unlike mRNA levels. These data identify an epigenetic mark of feminization that may serve as an indicator of not only estrogenic exposure but also previous exposure to EE2. Environ Toxicol Chem 2024;00:1-10. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Pharmacological Perspectives of 2‐alkoxy‐3‐Cyanopyridine Scaffolds: An Up‐to‐Date Review

AbstractThe 2‐alkoxy‐3‐cyanopyridine derivatives’ straightforward synthesis, ease of structural manipulation, and variety of intriguing biological activity continue to captivate medicinal chemists. A substantial body of research has demonstrated that these derivatives exhibit several intriguing biological characteristics, including anticancer, antibacterial, antidiabetic, antioxidant, vasorelaxant, antiviral, and anti‐inflammatory effects. Based on the basic skeleton of 2‐alkoxy‐3‐cyanopyridine, some lead compounds have been prepared with varied pharmaceutical characteristics. These served as excellent models for the development of novel medications since they showed potential in vitro and in vivo action against several cell lines that were both drug‐susceptible and drug‐resistant. To expand the use of 2‐alkoxy‐3‐cyanopyridine in biomedicine, though, a lot more efforts are essential. To combat medication resistance and boost specificity, potential hybrids that unite the 2‐alkoxy‐3‐cyanopyridine moiety with other pharmacophores are indeed required. This review offers a summary of pharmacological screening, including studies of pertinent structure‐activity connections, action mechanisms, and potential therapeutic use.

Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

N6-Adenosine methylation (m6A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40, which shows an equilibrium dissociation constant (Kd) of 49 nM. The crystal structure of the complex (1.6 Å resolution) validated the design. Compound 40 is selective against the cytoplasmic m6A-RNA readers YTHDF1-3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO-1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the THP-1 cell line provides evidence of YTHDC1 target engagement in the cell. The binding to YTHDC1 in the cell is further supported by the cellular thermal shift assay. Thus, ligand 40 is a tool compound for studying the role of YTHDC1 in AML.