Letters in Organic Chemistry - Volume 21, Issue 6, 2024

Computational modeling has become a crucial tool in drug design, offering efficiency and cost-effectiveness. This paper discusses the various computational modeling techniques used in drug design and their role in enabling efficient drug discovery strategies. Molecular docking predicts the binding affinity of a small molecule to a target protein, allowing the researchers to identify potential lead compounds and optimize their interactions. Molecular dynamics simulations provide insights into protein-ligand complexes, enabling the exploration of conformational changes, binding free energies, and fundamental protein-ligand interactions. Integrating computational modeling with machine learning algorithms, such as QSAR modeling and virtual screening, enables the prediction of compound properties and prioritizes potential drug candidates. High-performance computing resources and advanced algorithms are essential for accelerating drug design workflows, with parallel computing, cloud computing, and GPU acceleration reducing computational time. The paper also addresses the challenges and limitations of computational modeling in drug design, such as the accuracy of scoring functions, protein flexibility representation, and validation of predictive models. It emphasizes the need for experimental validation and iterative refinement of computational predictions to ensure the reliability and efficacy of designed drugs.

The benzimidazole scaffold is a promising nucleus for developing novel therapeutic agents for ulcer treatment. Its unique chemical structure provides desirable pharmacological properties, such as excellent bioavailability, metabolic stability, and low toxicity, making it an attractive candidate for ulcer treatment. Several benzimidazole derivatives have shown significant anti-ulcer activity in preclinical and clinical studies, acting through multiple pathways, including inhibition of gastric acid secretion, suppression of gastric inflammation, and promotion of mucosal protection. Some benzimidazole derivatives have also demonstrated anti-Helicobacter pylori activity, suggesting their potential for eradicating bacteria associated with ulcer formation. However, challenges such as poor solubility and limited selectivity remain. Various approaches, such as prodrug design and formulation optimization, have been explored to overcome these issues and improve the therapeutic profile of benzimidazole derivatives. Overall, the benzimidazole scaffold holds great promise as a nucleus for developing novel anti-ulcer agents. Further research and optimization efforts are needed to harness its full potential and translate it into effective treatments for ulcers. With continued advancements in medicinal chemistry and drug design, benzimidazole-based compounds may offer new therapeutic options for patients suffering from ulcers and related gastrointestinal disorders. Hence, this review highlights the knowledge about benzimidazole scaffold, the mechanism of ulcer formation, and various benzimidazole derivatives with anti-ulcer activity, which can be further studied in pre-clinical and clinical trials.

This review aims to shed light on the profound implications of Schiff Bases in combating a spectrum of pathogens by delving into their complex classification, synthesis, and reactions. The investigation also covers the varied molecular properties of Schiff bases, highlighting their potential use as chelating agents in coordination chemistry. Moreover, the investigation explores the discerning nature of Schiff Bases about metal ions and their adeptness in establishing intricate associations, highlighting their significance in metal coordination chemistry and specialized pharmaceutical transport mechanisms. Moreover, the review delves into the synthetic capacity of Schiff Bases, highlighting their importance in synthetic methodologies due to their exceptional adaptability, selectivity, and structural similarity to organic compounds. The methodology employs a rigorous systematic literature review to understand Schiff Bases comprehensively. This involves a meticulous analysis of various research articles and publications, allowing for a comprehensive exploration of the topic. The assessment of experimental investigations contributes to comprehending their molecular attributes, specificity for metal ions, and capacity for synthesis. The presented analysis amalgamates a multitude of sources to provide a nuanced and comprehensive viewpoint on the subject matter of Schiff Bases. The findings underscore the multifaceted utility of Schiff Bases in the fight against pathogens, their adaptability as chelating compounds, and their discerning affinity for metal ions. The examination of synthesis highlights their profound importance in synthetic methodologies and their striking resemblance to compounds found in living organisms. In conclusion, this analysis reveals Schiff Bases as highly adaptable compounds with potential in antimicrobial therapy, coordination chemistry, and precision drug delivery. The distinctive molecular attributes of these substances, functioning as chelators, contribute to their notable importance. The ability of Schiff bases to form complexes and their preference for metal ions highlight the wide range of applications for these molecules. Schiff Bases have a transformative effect on chemistry and medicine as we investigate their synthetic potential, driven by their versatility and structural similarity to biological compounds.

The enantioselective synthesis of chiral cis-3-hydroxyazetidin-2-ones mediated by Porcine Pancreatic Lipase (PPL) via hydrolysis of cis-3-(chloro acetoxy) azetidin-2-ones in the presence of a phosphate buffer (0.1M, pH = 7.2) in acetonitrile at a temperature range of 25-35 °C was optimized. Under the optimized reaction conditions, the influence of various electron withdrawing/donating/neutral groups on ester functionality of cis-3-(substituted acetoxy)azetidin-2- ones towards hydrolysis was extensively studied, and the bromoacetoxy, propanyloxy, and formyloxy groups provided moderate to good yields of 90%, 91%, and 81%, respectively. Moreover, the chiral cis-3-hydroxyazetidin-2-ones underwent acetylation, and their enantiomeric excess was assessed using the 1H NMR technique, employing chiral shift reagents. To gain insights into the active sites of the biocatalyst, molecular docking studies of compounds 5(a-i) with pancreatic lipase (PDB ID: 1LBS) were carried out. Additionally, the proposed interaction of substituents with the biocatalyst established the absolute stereochemistry of the target chiral cis-3-hydroxyazetidin-2-ones using Seebach's model in comparison to Jone's models.

1,7-dimethylxanthine is a critical intermediate in the pharmaceutical industry. In this paper, a scalable route for the synthesis of 1,7-dimethylxanthine was developed. The method included two steps: (1) acylation reaction of ethyl 4-amino-1-methyl-1H-imidazole-5- carboxylate was carried out by using commercially available methylcarbamoyl chloride as the starting material; (2) through cyclization of pyrimidine ring with aqueous sodium hydroxide, 1,7- dimethylxanthine was obtained with a total yield of 80%, and its HPLC purity was 99% by area. The method is very efficient and readily adaptable to kilogram scale, and because of the cyclization reaction process in aqueous conditions, this route is worthy of exploration for industrial application.

Novel Furan-ring Fused Chalcones (FFC) were synthesized using a radical cyclization reaction of α,β-unsaturated ketones with cyclic ketone as the model reaction to attain this goal. In this study, traditional and microwave-assisted methods for the efficient and cost-effective synthesis of furan-ring fused chalcones in mild reaction conditions are compared and optimized. The goal is to develop a reliable and adaptable synthetic technique that may be used to produce these useful chalcone derivatives quickly and effectively. The optimal experimental conditions for these reactions were carefully determined using two independent methodologies: conventional (Method A) and microwave (Method B). The results indicated that the proposed method B could be used effectively in the future to synthesize novel furans with short reaction times and acceptable yields (87-94 %), and products were purified by column chromatography and preparative thin layer chromatography (PTLC). All new compounds were characterized by ¹H-NMR, ¹³C-NMR, LC-MS, and elemental analyses.

This work presents a clean and convenient synthesis of various β-enaminones including 5,5- dimethyl-3-aminocyclohex-2-enones, in satisfactory to excellent yields from the condensation reaction of primary amines with β -dicarbonyls by employing T3P^® as a catalyst and performing the reaction under microwave irradiation and solvent-free conditions. These rapid reactions launched readily and stood a diversity of organic functional groups. A mixture of 1,3-dicarbonyl compound, primary amine and T3P^® (50% in AcOEt) was irradiated for an appropriate time under microwave at 80°C. After completing the reaction (TLC) and cooling to r.t., ethyl acetate and saturated aqueous NaHCO3 solution were added. The aqueous phase was extracted ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, and filtered, and the solvent was removed under reduced pressure to afford the product, which was recrystallized from diisopropyl ether. The presented results exhibit a better catalytic activity of T3P in the synthesis of enaminones. It could be concluded that T3P is the best catalyst as it took only a few minutes for the completion of the reaction with an excellent yield of product, which indicates T3P is more efficient, compared to other catalysts. A comparison of the efficiency of the present procedure with some heterogeneous solid catalysts was evaluated as well. Clearly, a higher yield was established in this procedure compared to other catalysts. Furthermore, the reaction of amines with dimedone was investigated as well, delivering excellent yields. The reaction catalyzed by T3P under microwave irradiation supplies a comprehensive method for the synthesis of enaminones. In this work, T3P is an effective, efficient and green catalyst, which forms the procedure economic, suitable, and safe with widespread application in the synthesis of enaminones.

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.