Pharmaceutical Molecules Research Articles

Enhancing thermostability of lysine hydroxylase via a semi-rational design

(2S,4R)-4-Hydroxylysine (4-OH-Lys), a derivative of L-lysine, possesses a unique chemical structure that makes it a crucial precursor for the synthesis of pharmaceutical molecules, with extensive applications in the pharmaceutical and biochemical industries. Lysine hydroxylase (K4H) catalyzes the conversion of L-lysine to 4-OH-Lys, offering advantages such as mild reaction conditions, straightforward reaction steps, good regioselectivity, and high catalytic efficiency compared to chemical synthesis and natural extraction methods. However, the low thermostability of K4H hinders its application in large-scale production. In this study, we employed a semi-rational design approach, guided by ΔΔG folding free energy calculations and message-passing neural networks to enhance the thermostability of K4H. After two rounds of evolution, we identified two beneficial mutants: M25 (S101P/Q257M) and M32 (Q257M/V298I). Thermostability assessments revealed that the half-lives (t1/2) of M25 and M32 at 40 °C were 23.9-fold and 13.3-fold higher than that of the wild-type (WT), with melting temperatures (Tm) exceeding those of WT by 4.2 °C and 8.3 °C, respectively. Molecular dynamics simulations illuminated the mechanisms underlying this enhanced thermostability. This work provides valuable insights into the thermostability of K4H and yields key mutants that are promising candidates for practical production of 4-OH-Lys.

Photoredox-Catalyzed Alkene Acylesterification with Acyloxime Esters via C-C and Tertiary C-O Bond Formation.

We describe an efficient acyl esterification method for alkenes utilizing acyloxime esters as bifunctional reagents featuring radical acylation and congested C-O bond formation. This approach is characterized by mild photoredox conditions, high step and atom economy, a broad substrate scope, and excellent regioselectivity. A variety of valuable α-acyl hindered alcohol esters, including those obtained via gram-scale synthesis and late-stage functionalization of pharmaceutical molecules, were presented, demonstrating its synthetic potential and practicability.

Photoredox/Sulfide Dual Catalysis for Modular Synthesis of Multi-substituted Furan Rings via Catalytic Indirect Reductive Quenching.

The catalytic indirect reductive quenching method is facilitated by a combination of Ir(III) photoredox and sulfide dual-catalysis system. This study demonstrated a method for synthesizing multi-substituted furans by using a photoredox/sulfide dual-catalysis system. This method enables the synthesis of various furan derivatives, including spirofurans and phthalans. The utility of this system was demonstrated through gram-scale synthesis of the pharmaceutical molecule talopram. Mechanistic studies and density functional theory calculations suggested the formation of sulfonium species via sulfide radical cations, followed by intramolecular cyclization to produce the desired furan derivatives.

Enantioselective Synthesis of Vicinal Diamines and β-Amino Amides by NiH-Catalyzed Hydroamidation of Alkenyl Amides

Enantioenriched diamines and β-amino amides are privileged scaffolds in organic and medicinal chemistry, which exhibit many applications in natural products and pharmaceutical molecules, as well as asymmetric catalysis. Catalytic asymmetric...

Merging halogen atom transfer, ring-expansion and oxidation by electron-rich arenediazonium salts: modular assembly of cyclohexenone derivatives.

As fundamental structural scaffolds in numerous natural products and pharmaceutical molecules, the construction of cyclohexenone architectures has remained a pivotal focus in organic chemistry. However, established strategies to synthesize cyclohexenone derivatives via Dowd-Beckwith ring-expansion reaction invariably involve the use of transition metals and photoirradiation. Herein, we present a novel transition-metal- and photoirradiation-free pathway to access such structures from α-iodomethyl β-keto esters with electron-rich arenediazonium salts as inexpensive radical initiators and oxidants under mild reaction conditions. The unique aspect of this reactivity is the integration of halogen atom transfer, ring-expansion, and oxidation in one-pot. Further investigation reveals that this method is applicable for modifying complex biologically active molecules, such as epiandrosterone derivatives.

Rapid Separation of Representative Monomer Compound Rutin From Natural Product by Molecularly Imprinted Macroporous Adsorption Resin.

Monomer compounds from natural products are the major source of active pharmaceutical molecules, which provide great opportunities for discovering of new drugs. However, natural products contain a large number of rather complex compounds. It is difficult to obtain high-purity monomer compounds from complex natural products. Herein, we developed molecularly imprinted macroporous adsorption resins (MIRs-PDA) for the selective adsorption of target monomer compounds from natural products. The response surface methodology was employed to optimize the fabrication parameters. The separation performance of MIRs-PDA for the representative monomer compound rutin was thoroughly studied. We found that MIRs-PDA presented large adsorption capacity (107.82mg/g), high selectivity (selectivity coefficient was 2.90), good repeatability, and reusability. MIRs-PDA can reach 78.5% equilibrium adsorption capacity in 20min, showing quick binding kinetic behavior. Furthermore, MIRs-PDA showed good selective and specific adsorption performance for rutin from a representative real sample of Fagopyrum tataricum extract solution. The study of the adsorption mechanism showed that the adsorption of rutin on MIRs-PDA was spontaneous and thermodynamically feasible. The kinetic parameters adapted well to the pseudo-second-order kinetic model, and there existed equivalent binding sites in MIRs-PDA. The MIRs-PDA show promising application prospects for the separation of monomer compounds in natural products.

Oxometallate-Based Ionic Liquid Catalyzed CO2-Promoted Hydration of Propargylic Alcohols for α-Hydroxy Ketones Synthesis.

α-Hydroxy ketones are a crucial class of organic compounds prevalent in natural products and pharmaceutical molecules. The CO2-promoted hydration of propargylic alcohols is an efficient method for the synthesis of α-hydroxy ketones. Herein, an ionic liquid (IL) was designed to catalyze this reaction individually under atmospheric CO2 pressure, volatile organic solvents, and additives. This IL, constructed from the molybdate anion, can be recycled from industrial (NH4)2MoO4 production wastewater, demonstrating its high tolerance to catalytic environments and significant potential for practical applications. To our knowledge, this is the first instance of an oxometallate-based IL catalyst being utilized for the CO2-promoted hydration of propargylic alcohols. Further mechanistic studies revealed the bifunctionality of this IL in activating both CO2 and substrates.

Design and development of quetiapine fumarate nanosuspension by media milling method

Introduction: The critical and complex properties of Biopharmaceutics Classification System Class II quetiapine fumarate active pharmaceutical ingredient molecules that complicate effective oral delivery of these active pharmaceutical ingredients include low aqueous solubility and reduced bioavailability. Objective: The objective of this investigation is to develop a nanosuspension formulation of quetiapine fumarate using media milling techniques to effectively reduce particle size and enhance dissolution rate. Method: Quetiapine fumarate Nano suspensions were prepared by the media milling method. The milling process was optimized by studying the effects of critical process parameters on the size of nanosuspension using a factorial design approach. The prepared nanosuspension is subjected to various characterization techniques such as Particle size, Zeta Potential, differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and in vitro dissolution rate assessment. Results: The obtained results demonstrate that the average particle size of the prepared nanosuspensions is 225 nm with a Polydispersity index of 0.530, while the average Zeta potential is -38.2 mv. The crystalline structure of quetiapine fumarate nano-suspension is evident from differential scanning calorimetry and X-ray powder diffraction. Conclusion: The dissolution rate of the nanosuspension is significantly faster than that of pure Quetiapine Fumarate, and the Cumulative drug release (%) of nanosuspension is higher than that of pure Quetiapine Fumarate , indicating that the use of nanotechnology can considerably enhance the dissolution rate.

Direct Accessing γ‑Pyridyl Tertiary Alcohols through Metal Free Three-Component Reactions

Herein, we introduce a novel method for synthesizing γ-pyridyl alcohols from readily accessible alcohols. This process is a metal-free, three-component reaction that elegantly combines alcohols, vinylarenes, and 4-cyanopyridine. The versatility of this reaction is showcased through its successful application in the late-stage functionalization of pharmaceutical molecules.

Combination of Biochar and Advanced Oxidation Processes for the Sustainable Elimination of Pharmaceuticals in Water

The presence of pharmaceuticals in aquatic ecosystems is an issue of increasing concern. Regardless of the low concentration of pharmaceuticals in water, they can have a toxic effect on both humans and aquatic organisms. Advanced oxidation processes (AOPs) have been described as a promising technique for eliminating pharmaceuticals due to their high efficiency. However, the cost associated with the application of these processes and their high reagents and energy requirements have affected the implementation of AOPs at large scales. Biochar has been suggested to be used as a catalyst in AOPs to overcome these limitations. Biochar is considered as an alternative heterogeneous catalyst thanks to its physicochemical characteristics like its specific surface area, porous structure, oxygen-containing functional groups, electrical conductivity, persistent free radicals (PFRs), modifiable properties, and structure defects. This carbonaceous material presents the capacity to activate oxidizing agents leading to the formation of radical species, which are needed to degrade pharmaceuticals. Additionally, AOP/biochar systems can destroy pharmaceutical molecules following a non-radical pathway. To enhance biochar catalytic performance, modifications have been suggested such as iron (Fe) impregnation, heteroatom doping, and supporting semiconductors on the biochar surface. Although biochar has been efficiently used in combination with several AOPs for the mineralization of pharmaceuticals from water, further research must be conducted to evaluate different regeneration techniques to increase biochar’s sustainable applicability and reduce the operational cost of the combined process. Moreover, operational conditions influencing the combined system are required to be evaluated to discern their effect and find conditions that maximize the degradation of pharmaceuticals by AOP/biochar systems.

Facile preparation of fluorine-functionalized covalent organic frameworks@SiO2 as stationary phase for chromatographic separation of pharmaceutical molecules

Facile preparation of fluorine-functionalized covalent organic frameworks@SiO2 as stationary phase for chromatographic separation of pharmaceutical molecules

Investigating the potential role of T helper 17 cells among women experiencing overweight and obesity and their possible therapeutic targeting of the RORγt molecule

Obesity is a growing healthcare problem globally. In Saudi Arabia, 24% of adults aged 15 years and above have been living with Obesity. It is considered a chronic inflammatory condition that is linked to a wide range of disorders including type 2 diabetes mellitus, insulin resistance and cardiovascular diseases. In this study, we aimed to assess the influence of obesity on the proportion of Th17 cells among healthy, overweight, and obese women in Saudi Arabia. Additionally, we aimed to explore potential ligands targeting the master transcription factor of Th17 cells: RORγt. A cross-sectional study was conducted, wherein their body mass index (BMI) and waist circumference (WC) were measured. The proportion of peripheral Th17 cells was determined using flow cytometry. We found a decrease in the proportion of peripheral Th17 among women with central obesity, though this was observed among overweight and obese participants. Interestingly, both BMI and WC were inversely correlated with the proportion of peripheral Th17 cells in women experiencing overweight or obesity, while no change was observed among healthy participants. Notably, the analysis revealed a significant moderate negative correlation between the proportion of Th17 cells and HbA1c levels, observed only among the overweight and obese participants. In this study, we identified three potential binding sites on RORγt molecules of Th17 cells, bound to 58 chemical ligands. The majority of the chemical structures (72.4%) were targeted binding pocket 1 of the RORγt molecule. These findings could provide a new insight to develop new pharmaceutical molecules targeting immune cells to combat obesity and related metabolic disorders.

Synthetic Approaches for the Construction of Chiral Aziridines

AbstractOptically active aziridines represent a pivotal class of rigid three‐membered nitrogen‐heterocyclic compounds found in natural products, pharmaceuticals, agrochemicals, and functional motifs, which have demonstrated outstanding practicability as therapeutic molecular frameworks, versatile synthetic endpoints, and functional materials in both academic and industrial communities. Recent years have witnessed a broad spectrum of prominent breakthroughs in the field of chiral aziridines due to the aziridine‐based rigid and three‐dimensional pharmacophores, which have resulted in streamlining the drug discovery process. Over the past few decades, particular attention has been directed towards the strategically efficient, versatile, and practical assembly of optically active aziridines. These synthesis approaches have demonstrated great potential in the context of the construction of pharmaceutical molecules, biologically and pharmacologically relevant natural products, and functional materials. In this review, several synthetic strategies for the assembly of chiral aziridines are summarized, which could be divided into five categories: (1) Introduction; (2) Construction of optically active aziridines via reactions of olefines with nitrene sources; (3) Construction of optically active aziridines via reactions of imines with carbenes; (4) Construction of optically active aziridines via reaction of azirines; (5) Construction of optically active aziridines via intramolecular cyclization of amine derivatives.

A New CuI/Oxalamide Catalytic System for the Large‐Scale Aerobic Oxidation of Alcohols

AbstractSince the report of oxamide ligands, they have been widely used for the efficient construction of various types of C−X (such as C, N, O and S) bonds. To evaluate whether the easily tunable electronic properties and unique coordination modes of oxamide ligands can also shine in the field of oxidation, we initiated a study on oxamide ligand/copper/air oxidation and applied it to the oxidation of alcohols to assess its practicality and potential applications. The practicality of this strategy was further verified through scale‐up reactions on a 100 mmol scale and gram‐scale derivatization of pharmaceutical molecules.

Advances in Biocatalysis for Sustainable Pharmaceutical Synthesis: Applications, Technological Progress, and Future Directions

Biocatalysis has emerged as a critical tool in pharmaceutical synthesis, offering a range of significant advancements in recent years. This paper provides a comprehensive review of biocatalysis applications in drug synthesis, emphasizing its role in enhancing the efficiency and environmental sustainability of producing complex pharmaceutical molecules. Through detailed case studies, including the biocatalytic synthesis of amoxicillin, paclitaxel, and ribavirin, the paper illustrates the superior reaction efficiency, selectivity, and reduced environmental impact achievable through biocatalysis. The technological advancements discussed include optimizing enzyme activity via genetic engineering, enhancing enzyme stability through covalent modification, and applying enzyme immobilization techniques. Furthermore, the integration of biocatalysis with green chemistry principles is explored, highlighting its potential to reduce harmful byproducts and energy consumption in industrial processes. The paper also delves into the future directions and challenges of scaling biocatalysis for broader industrial application. As an integral part of green chemistry, biocatalysis is poised to play a pivotal role in promoting sustainable development and minimizing environmental impact in the pharmaceutical industry.

Green Synthesis of 2-Mercapto 5,6-Dihydro-4H-1,3-Thiazines via Sequential C-S Couplings.

The six-membered N,S-heterocyclic 1,3-thiazines and their derivatives are widely acknowledged as pharmaceutical molecules with a wide range of biological activities. In this study, we developed a unique thiol-involved cascade reaction that enables the efficient construction of the 5,6-dihydro-4H-1,3-thiazine scaffold through consecutive intermolecular thiol-isothiocyanate and intramolecular thiol-halogen click reactions. Structurally diverse 2-mercapto dihydrothiazines including three antitumour candidates of bis-dihydrothiazines were readily obtained in high yields from the readily available thiols and 3-chloroisothiocyanate in the green solvent EtOH/H2O (1:1) using K2CO3 (0.6 equiv.) as the base. Between the two synthesis procedures investigated, the microwave-assisted reaction generally behaved more efficiently than that under routine heating conditions. Furthermore, DFT calculation confirmed the sequential addition-substitution mechanism. This cascade C-S coupling reaction methodology offers several advantages, including rapid completion, high reliability, easy purification, and benign conditions.

Synthesis of Non-canonical Tryptophan Variants via Rh-catalyzed C-H Functionalization of Anilines.

Tryptophan and its non-canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long-standing challenge. Here, we report a regioselective synthesis of non-canonical tryptophans bearing C4-C7 substituents via Rh-catalyzed annulation between structurally diverse tert-butyloxycarbonyl (Boc)-protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc-directed C-H metalation and demetalation to afford a wide range of C2-unsubstituted indole products in a redox-neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non-canonical tryptophan residues in a highly regioselective manner.

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

AbstractTryptophan and its non‐canonical variants play critical roles in pharmaceutical molecules and various enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long‐standing challenge. Here, we report a regioselective synthesis of non‐canonical tryptophans bearing C4−C7 substituents via Rh‐catalyzed annulation between structurally diverse tert‐butyloxycarbonyl (Boc)‐protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc‐directed C−H metalation and demetalation to afford a wide range of C2‐unsubstituted indole products in a redox‐neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non‐canonical tryptophan residues in a highly regioselective manner.

A Tandem Catalysis for Isoindolinone Synthesis over Single-Atom Pd/TiO2 Catalyst.

Developing an efficient strategy to replace the conventional synthesis method for producing isoindolinone (IIO) scaffold, a crucial structural motif for constructing pharmaceutical molecules, remains to be a great challenge. Herein, a single-atom Pd/TiO2 tandem catalysis has been developed for the IIO scaffold synthesis by using readily available phthalic anhydride (PA), ammonia, and H2. The single-atom Pd/TiO2 catalyst demonstrates superior catalytic performance, achieving a PA conversion of 99 %, an IIO selectivity of 91 %, and a turnover frequency (TOF) up to 4807 h-1. This exceptional performance can be attributed to the tandem catalysis between TiO2 support and single-atom Pd. The TiO2 efficiently catalyzes the conversion of PA with ammonia to form phthalimide (PAM), subsequently transformed into IIO over TiO2 through the reaction of PAM with NH3 and the spillover hydrogen species derived from single-atom Pd. Notably, NH3 functions not only as a reactant but also as a promoter to accelerate the reduction of amides combined with the Pd/TiO2 catalyst. This tandem catalysis of a single-atom Pd/TiO2 catalyst provides a promising strategy for the synthesis of the crucial IIO platform molecules.

PtCl2-Catalyzed Intramolecular Cyclization of α-Benzyl Allenoates to Afford Indenes and Furanones.

Indene and furanone are important ring structures widely present in active pharmaceutical molecules. Here, we have developed a straightforward method for the synthesis of indene and furanone via PtCl2-catalyzed intramolecular cyclization of α-benzyl allenoates. By altering the ester substitution pattern in the α-benzyl allenoates, we can regulate the reaction site, enabling two distinct intramolecular cyclization reactions that yield both indene and furanone products, respectively. For α-benzyl-substituted ethyl allenoate, the reaction proceeds via a 5-exo cyclization to form indene derivatives. In contrast, for α-benzyl-substituted tert-butyl allenoate, the reaction involves ester hydrolysis and intramolecular cyclization, yielding furanone products. This method operates efficiently under a 5 mol % PtCl2 catalyst and exhibits good tolerance toward various functional groups. Furthermore, furanone products can be obtained on a gram scale and further smoothly converted into 1,2-disubstituted furan.