Ardahan University

Mitochondrial biogenesis is essential for cellular energy balance and metabolic stability. Its dysregulation is linked to various metabolic and neurodegenerative diseases, making it a significant therapeutic target. Pharmacological approaches aimed at enhancing mitochondrial function have gained attention for their potential to restore cellular metabolism.

This review examines recent advancements in pharmacological strategies targeting mitochondrial biogenesis, focusing on the roles of PGC-1α, AMPK, and SIRT1, alongside novel therapeutic agents and drug delivery systems.

A systematic review of studies published between 2018 and 2023 was conducted using databases such as PubMed, Web of Science, and Elsevier. Keywords related to mitochondrial biogenesis and pharmacological modulation were used to identify relevant literature.

Various pharmacological agents, including resveratrol, curcumin, and metformin, activate mitochondrial biogenesis through different pathways. SIRT1 activators and AMPK agonists have shown promise in improving mitochondrial function. Advances in mitochondria-targeted drug delivery systems enhance therapeutic efficacy, yet challenges remain in clinical translation due to the complexity of mitochondrial regulation.

Pharmacological modulation of mitochondrial biogenesis holds therapeutic potential for metabolic and neurodegenerative diseases. While preclinical studies are promising, further research is needed to optimize drug efficacy, delivery methods, and personalized treatment strategies.

The rising incidence of type 2 diabetes mellitus (T2DM) and its related complications has created an urgent need for new therapeutic approaches. We herein describe the synthesis as well as biological investigation of a series of sixteen new phenolic Mannich base derivatives of thiazolidine-2,4-dione as α-glucosidase (α-Glu) and aldose reductase (ALR2) inhibitors, two crucial enzymes involved in T2DM and its complications. In vitro assays showed strong inhibitory activities, compound 12 (tetrahydroisoquinoline and α-methylcinnamyl substituted) exhibited the strongest inhibition of ALR2 (K_i: 0.024 µM); compound 10 (1-phenylpiperazine and α-methylcinnamyl substituted) displayed remarkable α-Glu inhibition (K_i: 0.370 µM). Computer-aided studies supported experimental observations and revealed key binding features like hydrogen bond, π-π stacking, and hydrophobic interactions, which were responsible for the exceptional binding capacity of the compound with the enzyme. Cytotoxicity assays performed on healthy cell lines (HUVEC and BEAS-B2) revealed that the tested compounds were non-toxic at inhibitory concentrations. ADME-T predictions indicated that compounds 10 and 12 satisfy key drug-likeness criteria, with favorable oral absorption and moderate solubility. These findings highlight the potential of compounds 10 and 12 as promising inhibitors for managing diabetes and its complications, providing a foundation for further optimization and therapeutic exploration.

New naphthyl-thiosemicarbazone derivatives (1-9) were obtained from 1-naphthaldehyde and numerous thiosemicarbazides. New naphthyl-thio/carbohydrazones (10-12) were prepared from 1-naphthaldehyde and various thio/carbohydrazides. FT-IR, ¹H NMR, ¹³C NMR, and elemental analysis were used to elucidate the structures of the newly obtained compounds. The inhibitory effects of these compounds against human carbonic anhydrase isoforms I and II (hCA I and hCA II) and acetylcholinesterase (AChE) were systematically evaluated. Several compounds exhibited potent inhibition, particularly derivatives bearing halogenated and electron-donating aromatic substituents. Among them, compound 11 demonstrated the strongest inhibition for all three enzymes, with K_I values of 52.42 nM (hCA I), 59.23 nM (hCA II), and 40.16 nM (AChE), surpassing the reference standards acetazolamide and tacrine. Structure-activity relationship (SAR) analysis highlighted the critical influence of substituent type and position on enzymatic activity. In addition, molecular docking simulations were conducted to elucidate the binding interactions of the most potent compound with hCA I, hCA II, and AChE enzymes. The docking results supported the in vitro findings, revealing favorable binding energies and key interactions such as π-π stacking and hydrogen bonding, especially for compound 11.