Current Organic Synthesis - Online First

Timolol maleate is clinically used for the treatment of hypertension, angina pectoris, tachycardia, and glaucoma.

The aim of this study was to enhance the safe use of timolol maleate and investigate a synthesis method for 3-S-timolol, a newly identified impurity in timolol API (Active Pharmaceutical Ingredients).

(S)-3-(tert-butylamino)propane-1,2-diol (1) was used as a raw material. 3-S-timolol maleate (7) was synthesized through a five-step reaction. Overall yield was 57.7%, with a purity of 98%.

The structure of the target compound was confirmed via analysis of its ¹H nuclear magnetic resonance, ¹³C nuclear magnetic resonance, and high-resolution mass spectrometry spectra.

The synthesis method was straightforward and yielded a high-purity product suitable for use as a reference in the analysis and identification of timolol maleate-related substances.

An efficient procedure was reported for the synthesis of novel hybrid dithiazoles 7 and thiazoles 15, in good yields, by applying hydrazonyl chlorides 4 with thiocarbohydrazone derivatives 3 and 12.

The thiazole derivatives were evaluated for their antimicrobial and antioxidant activities.

According to the results, thiazoles revealed marked potency as antimicrobial and antioxidant agents. Thus, 7a's DPPH radical scavenging activity was excellent (38.19±0.33 and 14.37±0.4) at concentrations of 2.0 and 1.0 mg/mL, respectively. In addition, compound 3 exhibited activity against all bacterial strains tested, as evidenced by inhibition zones measuring that ranged from 8.5±0.43 mm for E. faecalis to 16.5±0.43 mm for S. mutans.

The MIC results showed that compound 3 was effective against E. coli, S. aureus, E. faecalis, P. aeruginosa, and S. mutans at concentrations of 1.0, 1.0, 2.0, 1.0, and 1.0 mg/mL, respectively. Furthermore, molecular docking has shown lower binding energy with different types of interactions at the active sites of Dihydropteroate synthase, Sortase A, LasR, and penicillin-binding protein pockets, indicating that these compounds could inhibit the enzyme and cause promising antimicrobial effects.

The origin, synthesis, characterization and docking studies of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,1E,4E)-3-hydroxy-5-phenylpenta-1,4-dien-1-yl)cyclopentyl)-N-ethylhept-5-enamide, an impurity generated in the preparation of an anti-glaucoma agent-Bimatoprost has been described.

This impurity was controlled by employing 30% Pd/C, and the impurity level was brought to the permissible level, i.e., 0.03% (ICH guidelines) in the final drug preparation of Bimatoprost.

Finally, induced-fit docking calculations were performed to theoretically evaluate the binding efficiencies of these inhibitors in the crystal structure of Prostaglandin F synthase (PGFS).

There are negligible differences in RMSD and docking scores between the two ligands, which amount to only 0.18 Å and 0.313 kcal/mol, respectively. These findings strongly indicate that both ligands are likely to exhibit similar biological functions and efficiencies.

4,6-Diaryl-substituted pyrimidines have shown high inhibitory potency against phosphoinositide 3-kinases (PI3Ks), which are important targets in oncology. Inhibition of PI3Ks could potentially be a viable therapy for human cancers.

The synthesis of pyrimidinone and dihydropyrimidinone derivatives as well as a series of 2,4-diaryl-substituted pyrimidines were described. These compounds were synthesized by cyclocondensation of α-aminoamidines with various saturated carbonyl derivatives and their analogs.

Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted pyrimidines were synthesized by combining α-aminoamidines with various saturated carbonyl derivatives and their analogs. By adjusting the large substituents in the 2-position, we gained the ability to modify the therapeutic properties of the resulting compounds. The potential of the newly synthesized derivatives for cancer treatment was assessed using molecular docking calculations. The results of the docking calculations suggest that some of the synthesized diaryl derivatives of pyrimidine have a strong binding affinity towards PIK3γ, making them promising candidates for the development of new anticancer medications.

We synthesized some pyrimidinones, dihydropyrimidinones, and 2,4-diaryl-substituted pyrimidines by combining α-aminoamidines with various saturated carbonyl derivatives and similar compounds. Molecular docking results suggest that certain diaryl derivatives of pyrimidine have a strong binding affinity for PIK3γ. Moreover, diphenyl derivatives of pyrimidine exhibited dual inhibitory activity against PI3K and tubulin, showing promise for the development of next-generation microtubule-targeting agents for use in combination therapies.

The protection of the hydroxyl group as formamides is a crucial initial step in pharmaceutical synthesis.

In this study, we investigated the O-formylation of alcohols using dimethylformamide (DMF) in a mixture with a new magnetic nanocomposite Fe3O4@Chitosan/POCl2-x.

The results demonstrate that this core-shell heterogeneous nanocomposite facilitates the formation of alkylformate, yielding products with high efficiency ranging from 79% to 96% within a remarkably short reaction time of 1 to 12 hours at room temperature, depending on the substrate structure. Significantly, the presence of this nanocomposite exhibits remarkable selectivity, favoring the formylation of less hindered benzylic and aliphatic primary alcohols. However, bulkier alcohols and phenols exhibit lower reactivity under these conditions and thiols do not react. The simplicity of the work-up procedure, combined with the magnetic recyclability, makes it reusable and environmentally friendly.

This study highlights the efficacy of this novel magnetic nanocomposite in facilitating formylation reactions, emphasizing its potential for application in pharmaceutical synthesis and bio compounds. This is due to its attributes of non-toxic nature, stability, and significant advantages over conventional methodologies.