Ashot Saghyan’s research while affiliated with Yerevan State University and other places

The major challenge in synthesizing unsymmetrical 1,3-diynes lies in achieving high selectivity, as competing homocoupling reactions often complicate product isolation. To address this, we employed a Ni­(II) complex of the Schiff base derived from (S)-2 N-(N′-benzylprolyl)­aminobenzophenone (BPB) and propargylglycine to optimize the conditions for the Glaser coupling reaction. Systematic variations of the reaction parameters, including solvent, temperature, and reaction time, established an efficient protocol for synthesizing enantiomerically enriched α-amino acids. Mechanistic insights into the selectivity of the reaction were obtained through density functional theory (DFT) calculations, revealing that the stability of key intermediates, particularly O13, plays a crucial role in driving the reaction toward the heterocoupling product. The reaction mechanism, including alkyne deprotonation, copper oxidation, and water extrusion steps, was thoroughly examined. This study extended to various phenylacetylene derivatives and an aliphatic alkyne, demonstrating the necessity of tailored reaction conditions for each alkyne to achieve optimal results. The developed protocol offers a versatile and efficient approach for the synthesis of unsymmetrical 1,3-diynes and enantiomerically enriched α-amino acids, with products retaining their chiral integrity, as confirmed by NMR, chiral HPLC, and circular dichroism (CD) spectroscopy.

Antimicrobial resistance represents a significant global health threat, prompting the exploration of alternative therapeutic strategies. Antimicrobial peptides (AMPs) and lipopeptides are promising candidates due to their unique ability to disrupt bacterial cell membranes through mechanisms distinct from conventional antibiotics. These peptides are typically enhanced by motifs involving cationic amino acids, positive charge, and aromatic residues. Additionally, the conjugation of acyl chains to the N‐terminus of AMPs has been shown to improve their antimicrobial activity and selectivity. However, the susceptibility of peptides to enzymatic degradation presents a major limitation. To address this, we investigated the incorporation of non‐coded amino acids (NCAAs) to enhance peptide stability. Specifically, we synthesized the NCAA 2‐amino‐3‐(1 H ‐imidazol‐1‐yl)propanoic acid [His*], producing both enantiomers with high yield and optical purity. We then designed various analogs of ultra‐short AMPs by inserting His* at specific positions, evaluating their antimicrobial properties with different acyl chain lengths (C16 and C12) at the N‐terminus and the C‐terminus. We were able to identify a very promising candidate for applications ( P8 ) characterized by resistance to proteolysis and enhanced biological effectiveness.

This study delves into the impact of two synthetic non-natural amino acids, 7 and 8, on the structural dynamics of serum albumin and their potential significance in anticancer drug delivery systems. Crucially, the dihydrofuran-containing compound 7 has been identified to bind to the G-quadruplex (G4) DNA sequence 22-mer Pu22, a mimic of the proto-oncogene c-Myc, as ascertained by circular dichroism (CD) and UV spectroscopy. Our docking studies suggest that 7 binds to the G4 structure from the side of the G-quartet in a quasi-parallel manner, engaging in ten intermolecular interactions, including hydrogen bonds, π-lone pair and π-alkyl interactions. Notably, one interaction involves the heterocyclic ring of the compound. Compound 7 emerges as a notable structure modulator, showcasing a significant enhancement in protein α helix formation, as observed in a serum albumin binding CD experiment, and the capability to form supramolecular networks, as evidenced by dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM), with the added benefit of encapsulating the natural anticancer drug curcumin within its self-assemblies. Toxicity assessments on human fibroblast cell lines demonstrate that both compounds are non-toxic, highlighting their biocompatibility and potential for safe biomedical applications. Interestingly, the triazole-based compound 8 induces distinctive structural changes in serum albumins, elucidated through CD and UV spectra using bovine serum albumin (BSA) as a model albumin target.

In recent years, fungal infections have emerged as a significant health concern across veterinary species, especially in livestock such as cattle, where fungal diseases can result in considerable economic losses, as well as in humans. In particular, Aspergillus species, notably Aspergillus flavus and Aspergillus versicolor, are opportunistic pathogens that pose a threat to both animals and humans. This study focuses on the synthesis and antifungal evaluation of novel 9-fluorenylmethoxycarbonyl (Fmoc)-protected 1,2,4-triazolyl-α-amino acids and their dipeptides, designed to combat fungal pathogens. More in detail, we evaluated their antifungal activity against various species, including Aspergillus versicolor (ATCC 12134) and Aspergillus flavus (ATCC 10567). The results indicated that dipeptide 7a exhibited promising antifungal activity against Aspergillus versicolor with an IC50 value of 169.94 µM, demonstrating greater potency than fluconazole, a standard treatment for fungal infections, which showed an IC50 of 254.01 µM. Notably, dipeptide 7a showed slightly enhanced antifungal efficacy compared to fluconazole also in Aspergillus flavus (IC50 176.69 µM vs. 184.64 µM), suggesting that this dipeptide might be more potent even against this strain. Remarkably, 3a and 7a are also more potent than fluconazole against A. candidus 10711. On the other hand, the protected amino acid 3a demonstrated consistent inhibition across all tested Aspergillus strains, but with an IC50 value of 267.86 µM for Aspergillus flavus, it was less potent than fluconazole (IC50 184.64 µM), still showing some potential as a good antifungal molecule. Overall, our findings indicate that the synthesized 1,2,4-triazolyl derivatives 3a and 7a hold significant promise as potential antifungal agents in treating Aspergillus-induced diseases in cattle, as well as for broader applications in human health. Our mechanistic studies based on molecular docking revealed that compounds 3a and 7a bind to the same region of the sterol 14-α demethylase as fluconazole. Given the rising concerns about antifungal resistance, these amino acid derivatives, with their unique bioactive structures, could serve as a novel class of therapeutic agents. Further research into their in vivo efficacy and safety profiles is warranted to fully realize their potential as antifungal drugs in clinical and agricultural settings.

In recent years, fungal infections have emerged as a significant health concern across veterinary species, especially in livestock such as cattle, where fungal diseases can result in considerable economic losses. Aspergillus species, notably Aspergillus flavus and Aspergillus versicolor, are opportunistic pathogens that pose a threat to both animals and humans. In cattle, Aspergillus infections can lead to mycotic abortion, primarily in late pregnancy, and cause respiratory and gastrointestinal issues. As the incidence of such infections rises, effective antifungal therapies are needed, particularly in the face of increasing antifungal resistance. This study focuses on the synthesis and antifungal evaluation of novel Fmoc-protected 1,2,4-triazolyl-α-amino acids (5 and 6) and their dipeptides (8 and 9), designed to combat fungal pathogens with a targeted and po-tentially safer profile compared to traditional antifungal agents like fluconazole. Through opti-mized precipitation techniques and the activated ester method, we synthesized the compounds and evaluated their antifungal activity against Aspergillus versicolor (ATCC 12134) and Aspergillus flavus (ATCC 10567). The results showed that dipeptide (8) demonstrated promising antifungal activity at 0.16 mL, comparable to fluconazole, a standard treatment for fungal infections. Notably, increasing the concentration of fluconazole to 0.33 mL did not improve its antifungal efficacy, while the dipeptide's effect was enhanced with increased dosage, suggesting the potential of these dipeptides as more potent or selective antifungal agents. In contrast, the protected amino acid (5) exhibited consistent inhibition across all tested concentrations, aligning with the effects observed for fluconazole at higher concentrations. The increasing prevalence of fungal infections in im-munocompromised animals, coupled with the limited number of effective antifungal drugs, underscores the need for innovative therapeutic approaches. In cattle, Aspergillus infections can have devastating consequences for both animal health and agricultural productivity, with affected herds experiencing reduced milk production, poor fertility, and in severe cases, abortion. As conventional antifungal treatments may pose risks of resistance development or adverse side effects, novel antifungal peptides, such as the synthesized dipeptides in this study, present a promising alternative. These compounds offer the dual benefits of high bioactivity against pathogens like Aspergillus species and the potential for reduced resistance due to their distinct mechanisms of action. Our findings indicate that the synthesized 1,2,4-triazolyl dipeptides (8 and 9) hold significant promise as potential antifungal agents, not only for veterinary use in treating Aspergillus-induced diseases in cattle but also for broader applications in human and animal health. Given the rising concerns of antifungal resistance, these peptides, with their unique bio-active structures, could serve as a novel class of therapeutic agents with enhanced specificity and fewer side effects. Further research into their mechanism of action, in vivo efficacy, and safety profiles is warranted to fully realize their potential as antifungal drugs in clinical and agricultural settings.

The present study investigated the anion composition of drinking water from various cities and villages in Armenia, including spring water and tap water samples. The simultaneous separation was achieved for fluoride, chloride, bromide, nitrite, nitrate, sulfate, and phosphate anions with the correlation coefficients >0.998. Validation of the method was carried out in accordance with the requirements of guidelines in terms of selectivity, specificity, system suitability, linearity, accuracy, precision, lower limits of detection and quantitation, robustness, and stability. The method was suitable for routine drinking water quality assessment in line with the national or World Health Organization (WHO) regulations. The validated method was further used to analyze drinking water samples from different regions of Armenia. The observed concentrations for the anions in drinking water complied with the WHO limits for drinking water with some exceptions. The test method can be submitted to quality control laboratories as a convenient and practical tool for routine analysis and monitoring studies.