Investigation of the Experimental Pharmacokinetics of the Bis-Chlorinated Bis-pyridinium Mono-aldoxime Cholinesterase Reactivator K-868 in Rats

Background: The widespread use of organophosphorus compounds in agriculture and their existence in some military arsenals present continuous threats. Quaternary bis-pyridinium aldoximes are potent, highly polar cholinesterase reactivators and the most intensively studied candidate antidotes against poisoning with organophosphorus compounds. Objective: The in vivo experimental pharmacokinetic properties of K-868, a novel bis-chlorinated, bis-pyridinium mono-aldoxime are detailed and put in context with regard to similar compounds described earlier. Methods: Rats received 30 µmol K-868 i.m. and were sacrificed at various time points following treatment. Blood, cerebrospinal fluid and tear were collected, while the brains, eyes, kidneys, livers, lungs and testes were removed, dissected and homogenized. K-868 concentrations were determined using high performance liquid chromatography with ultraviolet absorption detection. Results: K-868 was detected in the eyes, kidneys, lungs and tear within 5 minutes in maximal serum concentrations attained 15 minutes following administration. Elimination was slow for K-868 which remained detectable at 120 minutes in the blood and the kidneys, and at 60 minutes in the eyes, lungs and tear following its administration. Nevertheless, its distribution was overall poor with areas under the 120-minute concentration curves (AUC120) showing close similarity in the blood and the kidneys, while reaching just approximately 5% of serum AUC120 in the eyes and lungs. Conclusion: K-868 is a potent candidate antidote against organophosphate poisoining with a prolonged presence in the circulation.

Synthesis of Medicinally Important Indole Derivatives: A Review

Indoles constitute a widely occurring functional group in nature and are present in an extensive number of bioactive natural products and medicinally important compounds. As a result, exponential increases in the development of novel methods for the formation of indole core along with site-specific indoles have been established. Conventional methods for the synthesis of indoles are getting replaced with green methods involving ionic liquids, water as a solvent, solid acid catalyst, microwave irradiation and the use of nanoparticles under solvent-free conditions. In addition, there are immense applications of the substituted indoles in diverse fields.

Synthesis of Medicinally Important Quinazolines and Their Derivatives: A Review

The study of biodynamic heterosystems has proved to be the most attractive and useful for the development of potential drugs with superior properties and works effectively for the treatment of a variety of diseases, including pandemic ones. Out of the thousand biodynamic heterosystems, the quinazoline heterosystem is one that exhibits wide-ranging biological and pharmacological properties. Synthesis of potential medicinal material is comparatively challenging and needed enough time for clinical trials, testing, permissions for concerned authorities, production and supply. Therefore, researchers usually focused on novel methods incorporated with a high yield of previously approved chemical compounds. This present review article has focused on the synthesis of medicinally important quinazolines and their derivatives, which produce reaction products in less time with high yields, including more attention with eco-friendly green synthesis approaches incorporating multicomponent reactions (MCR), ionic liquids and microwave irradiations.

Anti-diabetic Effect of Acridocarpus Orientalis

Background: Acridocarpus orientalis (AO) is a medicinal herb indigenous to tropical and subtropical Africa, Arabian Peninsula, and New Caledonia with reported anti-inflammatory and antioxidant properties. Objective: To determine whether AO has any beneficial effects on diabetes-induced metabolic parameters in rats. Materials and Methods: Diabetes mellitus was induced in male Wistar rats by streptozotocin. Diabetic rats were treated with three doses of AO extract (50, 100, and 200 mg/kg BW) for 30 days. Kidney, liver, and pancreatic tissue samples were processed for histopathology to determine the effect of AO on the cells of these organs. The effect of AO on pancreatic islet cells and serum insulin levels was also examined using immunohistochemistry and enzyme-linked immunosorbent assay techniques, respectively. Results: AO (100 mg/kg BW) caused a marked reduction in blood glucose levels in diabetic rats compared to diabetic control on day 10 of the study. Moreover, AO (200 mg/kg BW) increased the number of insulin-positive cells with a concomitant reduction in the number of glucagon-immunoreactive cells in pancreatic islets. AO (100 mg/kg) also increased the serum level of superoxide dismutase significantly. Although the administration of AO was able to significantly decrease the diabetes-associated increases in serum creatinine and bilirubin levels, it had no effect on blood urea nitrogen, serum aspartate, or alanine aminotransferase levels. Histopathological examination showed that AO has no toxic effect on the structure of the pancreas, liver, and kidney. Conclusion: Our findings showed that AO could alleviate some complications of diabetes mellitus.

Study on the Interaction of 4'-Hydroxychalcones and their Mannich Derivatives with Calf Thymus DNA by TLC and Spectroscopic Methods, a DNA Cleavage Study

Background: Phenolic Mannich bases derived from hydroxychalcones show remarkable cytotoxic potencies towards cancer cell lines. However, the exact mechanism of action is still partially uncleared. Objective: Interaction of two hydroxychalcones and their Mannich derivatives with calf thymus DNA (ctDNA) has been investigated. Methods: Thin-layer chromatography and UV-Vis spectroscopic method were used for studying the interaction. The binding constant has been determined by UV-Vis spectrophotometric titration. The DNA cleavage activity of the compounds was studied by agarose gel electrophoresis. Results: Interaction of the compounds with ctDNA exhibited relatively high intrinsic binding constant (4-5x104 M-1). The results indicate existence of weak, non-covalent interactions between the investigated derivatives with ctDNA. Some compounds showed a slight DNA cleavage activity with pBR322. Conclusion: The obtained results provide additional knowledge on the previously documented cytotoxicity against tumor cell lines of the hydroxychalcones and their Mannich-derivatives.

Pharmacokinetics of a Mono-pyridinium-mono-aldoxime (K-347), a Potential Antidote in Organophosphate Poisoning

Background: Our recent work has been treating the pharmacokinetics of pyridinium aldoximes of various structures including their time-dependent distribution in the body of male rats and also the extent of blood-brain-barrier penetration. Objective: Our overall aim was to find a proper antidote in organophosphate poisoning with fast elimination. Methods: White male Wistar rats were intramuscularly injected with the aqueous solution of 3 µmol of K-347. The animals were sacrificed at different time periods following treatment; various tissues and body fluids were taken and homogenised. The level of K-347 was determined using reversed-phase HPLC. Dose-dependence of tissue level was also determined by using various doses, 3 µmol through 100 µmol of K-347. Results: The serum level of K-347 showed a definitely fast decline. K347 did not have any effect on Gram-positive and Gram-negative bacteria that we tested. Conclusion: The kinetics of K-347 showed an extremely fast offset, even in comparison with several other pyridinium aldoximes in clinical practice and in developmental stages.

Antiviral Activity of Benzotriazole Based Derivatives

Background: For the last thirty years, the benzotriazole scaffold has been the object of our group interest and we have already presented some results on the antiviral activity of our compounds. Objective: In this article, we conclude the exploration of N-(4-(R-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)-4-R’-benzamides and 1-(4-(R-2H-benzo[d][1,2,3]triazol-2-yl)phenyl)-3-R’-ureas by synthesizing further modified derivatives, in order to have more elements for SARs evaluation. Methods: Here, we reported the synthesis and the antiviral screening results of 38 newly synthesized benzotriazole derivatives against a panel of DNA and RNA viruses. We also analyse SARs in comparing these compounds with previously published benzotriazole analogues, taking stock of the situation. Results: Among the newly presented derivatives, compounds 17 and 18 were the most active with EC50 6.9 and 5.5 µM, respectively against Coxsackievirus B5 (CV-B5) and 20.5 and 17.5 µM against Poliovirus (Sb-1). Conclusion: we can conclude that N-(4-(2H-benzo[d] [1 - 3] triazol-2-yl)phenyl-R-amide is a good chemical scaffold for the development of new antiviral molecules.

Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds

Background: Pestivirus genus includes animal pathogens which are involved in economic impact for the livestock industry. Among others, Bovine Viral Diarrhoea Virus (BVDV) establish a persistent infection in cattle causing a long list of symptoms and a high mortality rate. In the last decades, we synthesised and reported a certain number of anti-BVDV compounds. Methods: In them, imidazoquinoline derivatives turned out as the most active. Their mechanism of actions has been deeply investigated, BVDV RNA-dependent RNA polymerase (RpRd) resulted as target and the way of binding was predicted in silico through three main H-bond interaction with the target. The prediction could be confirmed by target or ligand mutation. The first approach has already been performed and published confirming the in silico prediction. Results: Here, we present how the ligand chemical modification affects the anti-BVDV activity. The designed compounds were synthesised and tested against BVDV as in silico assay negative control. Conclusion: The antiviral results confirmed the predicted mechanism of action, as the newly synthesised compounds resulted not active in the in vitro BVDV infection inhibition.