Current Organic Synthesis - Volume 22, Issue 6, 2025

α-Glucosidase inhibitors play an important role in the treatment of type 2 diabetes mellitus. Inhibitors of the latter enzyme that are available on the market created gastrointestinal side effects and achieve to a high potent and low side effect potent α-glucosidase inhibitors is a valuable target for medicinal chemists.

In this study, derivatives of benzimidazole-phenoxy-1,2,3-triazole-benzyl skeleton were introduced as new α-glucosidase inhibitors.

Twelve derivatives 8a-l of target scaffold were synthesized via simple chemical reactions with a yield between 65 and 88%. The in vitro α-glucosidase inhibition activities of these compounds was evaluated against yeast form of this enzyme. After the determination of most potent compound, the interaction of this compound with α-glucosidase was evaluated in vitro by kinetic study and in silico by docking study. Drug-likeness, pharmacokinetics, and toxicity profiles of the most potent compound were predicted by an online software.

Anti-α-glucosidase assay demonstrated that all synthesized derivatives 8a-l were more potent that standard inhibitor acarbose. Representatively, 2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole (compound 8a) as the most potent derivative was 150-times more potent than positive control. Kinetic study of compound 8a revealed that this compound is an uncompetitive inhibitor against α-glucosidase. Furthermore, molecular docking study showed that compound 8a with favorable binding energy attached to important residues in the α-glucosidase active site. This compound also can be an oral drug with favorable toxicity profile.

Benzimidazole-phenoxy-1,2,3-triazole-benzyl derivatives 8a-l synthesized and evaluated for anti-α-glucosidase activity. All these compounds were excellent α-glucosidase inhibitor, and compound 8a demonstrated the most significant inhibition effect when compared with positive control.

Ripasudil hydrochloride or 4-Fluoro-5-{[(2S)-2-Methyl-1,4-diazepan-1-yl] sulfonyl isoquinoline hydrochloride known as K-115 is used for the treatment of glaucoma and ocular hypertension. In the API industry, to achieve and ensure the quality of drug substances, there is a need for impurity identification, synthesis, and characterization. The impurities are formed during the process, either side reaction or degradation or carried over from the starting material.

The present study explores two new process impurities of Ripasudil Hydrochloride dihydrate, specifically Impurity-1(4-fluoro-5-{[(3R)-3-methyl-4-(2-nitrolbenzenesulfonyl)-1,4-diazepan-1-yl] sulfonyl} isoquino line) and Impurity-2 (4-fluoro-N, N-dimethyl isoquinoline-5-sulfonamide). These impurities are critical to the quality of both the drug substance and the final drug product.

The API crude samples were subjected to LC-mass spectrometry for the identification of unknown impurities and further based on the observed mass values, a strategic synthetic route was designed for the synthesis of unknown impurities. The synthetic routes for these impurities were developed to avoid column purification, achieving high yields and purity.

The above synthesized impurities were subjected to spectral analysis like mass spectrometry, ¹H NMR, and ¹³C NMR and confirmed the desired structure of the unknown impurities. So, as far as we know, the two impurities are new process impurities and have not been reported in the literature.

The two new process impurities have been prepared and used as impurities for the method development and quality evaluation of the Ripasudil drug substance. Given the regulatory significance of Ripasudil hydrochloride, our successful synthesis and characterization efforts have proven to be valuable. This research offers valuable insights into the generic pharmaceutical industry.

Nitrogen mustards exert their anticancer activity by alkylating DNA. However, except for alkylating DNA, nitrogen mustards may alkylate other biomolecules to cause off-target effects due to their highly active functional groups. So, more exposure of DNA from chromosomes can facilitate the binding of nitrogen mustards to DNA to present stronger anticancer activity, simultaneously avoiding more side effects.

To design and synthesize the 4-phenylbutanoic acid-chlorambucil conjugates and valproic acid-chlorambucil conjugates. Upon cellular internalization, the two conjugates can more strongly damage the DNA of cancer cells due to the more exposure of cellular DNA caused by 4-phenylbutanoic acid or valproic acid.

To validate this hypothesis, we designed and synthesized two hybrids of chlorambucil with 4-phenylbutanoic acid and valproic acid, denoted as compound 2a and compound 2b respectively. The antitumor activity of the aforementioned hybrids was evaluated by the MTT method, mitochondrial membrane potential analysis, apoptosis assay, DNA damage assay, and scratch assay respectively.

Compound 2a and compound 2b were synthesized via esterification. The results of bioactivity evaluation showed compound 2a and compound 2b had stronger cytotoxicity against breast cancer MDA-MB-231 cells and MCF-7 cells than chlorambucil. More importantly, toward triple negative breast cancer MDA-MB-231 cells, compound 2a exhibited significantly greater cytotoxicity compared to both compound 2b and chlorambucil. Further studies were conducted on MDA-MB-231 cells, showing that compound 2a could more strongly decrease the mitochondrial membrane potential, induce cell apoptosis, and damage cellular DNA compared to compound 2b and chlorambucil. Interestingly, in combating the migration of MDA-MB-231 cells, the results exhibited that compound 2b had a much stronger anti-migratory effect than compound 2a, inconsistent with the aforementioned in vitro cytotoxicity.

These findings demonstrate that the combination of nitrogen mustards with histone deacetylase inhibitors is an effective strategy to exert synergistic anti-tumor effects.

1,4-oxazepine is a significant structural motif found in several bioactive molecules used in the treatment of diseases such as psychotic disorders.

Therefore, developing novel methodologies for its preparation is of great interest to medicinal chemists.

These seven-membered heterocycles are generated through the intramolecular cyclization of Betti bases, which are propargylated using propargyl bromide as the source of the triple bond in the presence of a base.

This efficient and straightforward protocol proceeds under mild, metal-free conditions and has been shown to be applicable to a broad range of aldehydes and 2-aminopyridines.

o-Aminophenol derivatives are of particular interest for their diverse biological activities and potential therapeutic applications. Such as, antioxidant, antibacterial, and cytotoxic activities.

This study aimed to design and synthesize a series of novel o-aminophenol derivatives through an efficient multi-step process, characterize them using modern spectroscopic techniques, and evaluate their antimicrobial, antioxidant, and cytotoxic activities.

A series of novel derivatives of o-aminophenol have been successfully synthesized with very high efficiency through a simple six-step process using readily available chemicals and straightforward reactions. The structures of all products were accurately determined using modern spectroscopic methods such as 1D and 2D NMR, as well as IR, MS spectroscopy, and X-ray methods. The antimicrobial activities of eight o-nitrophenol derivatives were assessed against Gram (-) and Gram (+) bacteria as well as fungi. In comparison, antioxidant activities were tested for two o-nitrophenol and 11 o-aminophenol derivatives using SC50 and EC50 assays. Cytotoxicity was evaluated on KB, HepG2, A549, and MCF7 cancer cell lines.

Six synthesized compounds 5b, 5c, 5g, 6b, 6c, 6g exhibited unusual doublet signals in the H8 region of the ¹H NMR spectrum, attributed to atropisomer formation. Eight o-nitrophenol derivatives demonstrated weak antimicrobial activity, with MIC values ranging from 100 to 200 µg/mL. Compound 5g showed activity against all tested bacterial and fungal strains. In antioxidant testing, eight o-aminophenol derivatives 6a, 6b, 6c, 6e, 6f, 6h, 6i, and 12b displayed excellent activity, with SC50 values between 18.95 and 34.26 µg/mL, approaching ascorbic acid's SC50 value of 12.60 µg/mL. Three derivatives 6d, 6g, and 12a showed superior antioxidant activity with EC50 values between 4.00 and 11.25 µg/mL, surpassing quercetin's standard of 9.8 µg/mL. Cytotoxicity assays revealed that o-aminophenol derivatives 6b, 6c, 6f, 6i, and 12b exhibited moderate inhibitory effects on KB cell lines with IC50 values from 32 to 74.94 µg/mL. Compound 6i demonstrated moderate cytotoxic activity against HepG2, A549, and MCF7 cell lines, with IC50 values of 29.46, 71.29, and 80.02 µg/mL, respectively.

Design, synthesis, antimicrobial activity, DPPH Radical Scavenging, Cytotoxic activity, Evaluation of H8 signal anomalies in certain compounds, and Single crystal X-ray diffraction analysis.

This research introduces an eco-friendly, one-pot multicomponent synthesis of pyrimidopyrimidines (4a-4i) and amino-1,3-dimethylpyrimidines (5a-5d) in an aqueous medium, utilizing citric acid as a catalyst.

The study aimed to establish a sustainable method for synthesizing these heterocyclic compounds while evaluating their biological activities.

Structural characterization of the synthesized compounds was conducted through elemental analysis, IR, and NMR spectroscopy. The DPPH, TAC, and ABTS methods assessed the antioxidant properties, revealing their significant potential as bioactive agents. Compound 4i demonstrated the highest antioxidant activity with a DPPH inhibition of 99.13%, while compound 5b exhibited the highest ABTS activity of 100%. Advanced computational analysis using Density Functional Theory (DFT) at the B3LYP/6-311+G(d,p) level provided insights into the compounds' molecular structures, reactivity, and electronic properties.

Key findings include the energy band gap analysis, which revealed compound 4c as the most stable (energy gap 5.102 eV) and compound 4i as the most reactive (energy gap 3.51 eV). These theoretical calculations, aligned with experimental NMR data, validated the molecular structures and confirmed the accuracy of theoretical predictions. Additionally, antibacterial and antifungal assays identified compound 4i as the most effective against Gram-positive and Gram-negative bacteria and Candida albicans.

This work highlights the potential of these derivatives as promising candidates for therapeutic applications and contributes to advancing environmentally benign synthetic methodologies.