Antiamnestic effect of new nicotinic acid derivatives

Introduction: The search for new drugs for the prevention and treatment of vascular cognitive disorders continues to be a relevant task of pharmacology. In this regard, the aim of this work is to study the antiamnestic effect of five new nicotinic acid derivatives in comparison with the well-known drug mexidol (ethylmethylhydroxypyridine succinate) in animals. Materials and methods: The experiments were carried out on white male mice using conditioned passive avoidance reflex (CPAR). Electroconvulsive shock (ECS), scopolamine administration, and acute hypoxia in a hermetic chamber were used as amnesic effects. Testing for the safety of CPAR was performed 24 h after amnesic exposure. The new substances, reference drug mexidol, and a 0.9% sodium chloride solution (control group) were administered once intraperitoneally 60 min before mice training. Results and discussion: Three of the five new nicotinic acid derivatives, LKhT 4-19 (100 mg/kg), LKhT 6-19 (25, 50, and 100 mg/kg), and LKhT 7-19 (100 mg/kg), have antiamnestic properties on models of amnesia in mice induced by ESC, scopolamine, and acute hypoxia in a hermetic chamber. At the same time, the most efficient substance – LKhT 6-19 – exceeds the reference drug mexidol on all three models used. In addition, this compound is also more efficient than two other new compounds, LKhT 4-19 and LKhT 7-19, on the model of ESC-induced amnesia and LKhT 7-19 on the scopolamine-induced amnesia model. Conclusion: Compound LKhT 6-19 is promising for further advanced preclinical studies as a potential drug with antiamnestic activity. Graphical abstract:

2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication

The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.

INVESTIGATION OF THE ANTIHYPOXIC PROPERTIES OF NEW NICOTINIC ACID DERIVATIVES

Two of the five new nicotinic acid derivatives proved to have the antihypoxic properties in tests with mice exposed to acute normobaric hypoxic hypoxia with hypercapnia. Specifically, LKhT 4–19 (100 mg/kg) extended lifetime of the animals by 11 %; LKhT 6-19 doses of 50 and 100 mg/kg extended lifetime by 23 and 34 %, respectively. The antihypoxic effect of LKhT 6–19 (50 mg/kg) outperformed in 1.2 times mexidol (substance of comparison) at the similar dose and was highly competitive at the dose of 100 mg/kg. For reference, mexidol is a 3-hydroxypyridine derivative (ethylmethylhydroxypyridine succinate incorporating, similar to the substances in question, the pyrydine heterocycle). Besides, LKhT 6–19 (100 mg/kg) outperformed mexidol at the similar dose in 1.1 times.

Partial Validation of High Performance Liquid Chromatography for Analysis of Isoniazid in Rat Plasma

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Nicotinic acid derivatives such as isoniazid have the strongest anti-tuberculosis properties. For pharmacokinetics studying of isoniazid (INH), a method is needed to determine the levels of INH in plasma. Objective: The aim of this research is to partial validate of high performance liquid chromatography (HPLC) for analysis of INH in rat plasma. Method: For the preliminary study, rat plasma was used. The HPLC system used is a stationary phase C18 with length 250mm and temperature of 30°C, mobile phase hexane sulphonate acid 20mM pH 2.47–methanol (65:35). The analytical parameters in partial validated were linearity, lower limit of quantification (LLOQ), precision, accuracy, and recovery. Results: The results of linearity test of INH showed r value of 0.9996. LLOQ of this method was 0.1258μg/mL. The resulting accuracy and precision value met FDA requirements with a percent recovery ranging from 96.57–107.99%. Conclusion: The HPLC system was a valid method for analysis of INH in rat plasma.

Domino reaction of cyclic sulfamidate imines with Morita–Baylis–Hillman acetates promoted by DABCO: a metal-free approach to functionalized nicotinic acid derivatives

A series of 4,6-diarylnicotinates have been prepared in good to excellent yields via a domino reaction of cyclic sulfamidate imines with MBH acetates in 2-MeTHF promoted by DABCO under an O2 atmosphere.