Yunusov Institute of the Chemistry of Plant Substances

Benzimidazole derivatives possess potential biological activity, and modern methods are required for the synthesis of new derivatives in high yields. The aim of this study was to obtain new benzimidazole derivatives through acylation of carbendazim (1) with aliphatic carboxylic acids, then carry out the reactions of nitration, reduction and acylation of acyl-derivatives, and studying chemical structure and cytotoxic activity of the obtained compounds. The resulting acyl compounds (2 and 3) were nitrated to synthesize 6-nitro derivatives (4 and 5) in high yields. Their reduction gave 6-aminobenzimidazole derivatives (6 and 7), respectively. The yield of the synthesized compound (6) was 72.1%, and that of compound (7) was 93%. Compounds (6) and (7) were acylated with aliphatic carboxylic acids to obtain bis-acyl products. It is worth noting that selective acylation of the amino group at position 6 of the benzimidazole molecule led to the formation of amides (8-14) in 79-92% yields. Only the reaction of compound (6) with glacial acetic acid led to the formation of triacetamide (8) in 92% yield. The synthesized all compounds were characterized by 1H, 13C NMR, IR spectral data. Additionally, synthesized benzimidazole derivatives were evaluated for their cytotoxic activity against triple-negative breast cancer cell lines (BT-20, MDA-MB-231, HCC1395) and the noncancerous HEK293 line using the MTT assay. Most compounds showed low cytotoxicity (IC₅₀ > 50 μM), while derivatives (9) and (10) exhibited moderate activity suggesting that the presence of ethyl (9) or propyl (10) groups at position 2 of the imidazole ring influences the anticancer potential.

This study investigates the mitochondrial effects and pharmacokinetic profile of 3,5,7,2’,6’-pentahydroxyflavanone (PHF), a naturally occurring flavonoid. In vitro results showed that PHF at 40 and 60 µg/mg protein reduced glutamate-supported state 3 respiration by 6% - 10% and slightly increased state 4 respiration, leading to a decrease in respiratory control ratio (RCR) and ADP/O ratio. For succinate as substrate, PHF at the same doses reduced V3, V4, and VDNP respiration rates by 15% - 33% and increased the ADP/O ratio up to 1.44-fold, indicating enhanced coupling efficiency. Enzymatic assays revealed that PHF selectively suppressed succinate dehydrogenase and oxidase activities by up to 25% without affecting NADH-linked enzyme systems. Notably, PHF reduced mitochondrial calcium uptake by 10.7% - 47.8% in a dose-dependent manner (100 - 500 mg/kg, i.p.) and attenuated the activity of membrane-bound oxidases under phospholipase A2 stress, suggesting membrane-stabilizing effects. ADMETlab predictions indicated favorable drug-like properties (MW 286.05, logP 2.25, TPSA 111.13), high plasma protein binding (PPB 95.2%), and acceptable oral bioavailability (F50%: +++). PHF was predicted to inhibit CYP1A2, CYP2D6, and CYP3A4 enzymes but not act as their substrate. Toxicity alerts were minimal, though genotoxicity (0.956) and eye irritation (0.996) probabilities were elevated. Taken together, PHF demonstrates mitochondria-targeted bioactivity and a moderate ADMET profile, positioning it as a potential lead compound for cytoprotective drug development. HIGHLIGHTS 3,5,7,2’,6’-Pentahydroxyflavanone (PHF) selectively modulates mitochondrial respiration depending on the substrate used. PHF decreases glutamate-supported oxidative phosphorylation and enhances coupling efficiency during succinate oxidation. The compound significantly reduces mitochondrial Ca2+ accumulation in a dose-dependent manner (up to 47.8%). PHF stabilizes mitochondrial membrane enzymes under thermal and phospholipase A2-induced stress. ADMET profiling confirms PHF has favorable drug-likeness, low cardiotoxicity, and high predicted oral bioavailability. PHF exhibits selective interaction with CYP450 enzymes and low toxicity alerts, supporting its drug development potential. GRAPHICAL ABSTRACT

The main problem with conserving introduced plants in botanical gardens is that more than 45% of species exist as isolated specimens, many of which cannot be propagated by seed or cuttings. Microclonal propagation offers a promising solution that allows rapid propagation of rare and valuable plant material. Ungernia sewertzowii (US) is a medicinal plant rich in alkaloids, particularly lycorine (0.04–0.46% in leaves, 0.15–0.38% in bulbs), used for bronchitis treatment. Due to overharvesting, natural populations are at risk, necessitating in vitro propagation as an alternative source of raw material. Callus induction was achieved on Murashige and Skoog (MS) medium with 2,4-D (0.5 mg/l) combined with BAP, Kin, or Zea (0.5 mg/l each). Organogenesis, both direct and indirect, was observed on MS with BAP or Kin (0.5 mg/l) supplemented with IAA or NAA (0.5 mg/l). These protocols enable sustainable production of bioactive compounds while conserving wild populations.

Derivatives of 1,2,4-triazole-3-thione exhibit a variety of biological activities, including antimicrobial (e.g., compounds 31d–k, 32d, 36f), antitumor (e.g., 71, 77a–c, 82g, 94h), anti-inflammatory, analgesic (100a, 102, 105), antidiabetic, and antioxidant (104, 138) activity. These compounds can be efficiently synthesized by classical methods (e.g., cyclization of thiosemicarbazides) and/or modern “green” approaches, which allow for obtaining target compounds in high yields (up to 96%). The presence of electron-donating groups (e.g., -OH, -OCH3) enhances antimicrobial and antitumor activity. Substituents in the aromatic ring (e.g., NO2, Cl) affect the ability to bind to biological targets such as DNA or enzymes. 1,2,4-triazole-3-thiones can also be used as fungicides and herbicides (e.g., 131), demonstrating high efficiency against phytopathogens. Thus, 1,2,4-triazole-3-thione derivatives are multifunctional compounds with high potential for the development of new drugs and agrochemicals. Their further study and modification can lead to the creation of more effective and safer drugs.