Approx. 75% of modern low-molecular-mass pharmaceutical agents contain heterocyclic fragments. 5-Chloropyridine and its derivatives have been investigated for their potential antimicrobial, anticancer, anti-inflammatory, and antiviral properties. Pyridine moiety is often found in therapeutic agents due to its ability to effectively interact with biological targets. The prediction of ADMET parameters is a crucial aspect of drug discovery and development; it plays a significant role in optimizing the pharmacokinetic properties of novel drug candidates. This work aimed to synthesize biologically active compounds bearing 2-aminopyridine moiety and evaluate them as potential drug candidates based on their ADMET properties [1].
Reaction of 2-amino-5-chloropyridine with itaconic acid in water resulted in formation of 1-(5-chloropyridin-2-yl)-5-oxopyrrolidine-3-carboxylic acid, which subsequent reaction with hydrazine hydrate in DMF provided hydrazide 1. Hydrazide 1 reacted with various aldehydes to provide hydrazones 2–7 [2,3]. To assess their drug-likeness and pharmaceutical properties, pharmacokinetic profiles were calculated using in silico software AdmetLab 2.0. The molecular weight (MW) of all compounds falls within an acceptable range for oral bioavailability (346.1–420). Log P values for compounds 2-5 are in the range of 3.5–4.17 indicating moderate lipophilicity suitable for absorption, while they are slightly lower for 6, 7 suggesting an improved water solubility. Total polar surface area (TPSA) values range from 57.59 to 117.8. Lower TPSA values for 2, 3, and 7 suggest better permeability, while 5 and 6 may face challenges in intestinal absorption due to higher TPSA. Blood-brain barrier (BBB) permeability is the highest for 2, 5, and 7 (>0.9) suggesting potential for CNS-targeting, while 6 is unlikely to penetrate the BBB. Compound 6 shows the highest value (0.01) for human intestinal absorption (HIA).
Thus, six new compounds, bearing 2-amino-5-chloropyridine and hydrazone moieties, were synthesized. Evaluation of their ADMET properties has suggested that compound 5, bearing dimethylamino substituent, exhibits the most balanced pharmacokinetic profile with high blood-brain barrier permeability and moderate intestinal absorption, making it a promising candidate for further development. Its favorable lipophilicity and permeability suggest strong potential for both systemic and CNS targeting.