Quantitative Measurements of Pharmacological and Toxicological Activity of Molecules

Toxicity and pharmacological activity scales of molecules, in particular toxicants, xenobiotics, drugs, nutraceuticals, etc., are described by multiples indicators, and the most popular is the median lethal dose (LD50). At the molecular level, reversible inhibition or binding constants provide unique information on the potential activity of molecules. The important problem concerning the meaningfulness of IC50 for irreversible ligands/inhibitors is emphasized. Definitions and principles for determination of these quantitative parameters are briefly introduced in this article. Special attention is devoted to the relationships between these indicators. Finally, different approaches making it possible to link pharmacological and toxicological properties of molecules in terms of molecular interactions (or chemical reactions) with their biological targets are briefly examined. Experimental trends for future high-throughput screening of active molecules are pointed out

Quantitative Measurements of Pharmacological and Toxicological Activity of Molecules

Toxicity and pharmacological activity scales of molecules, in particular toxicants, xenobiotics, drugs, nutraceuticals, etc., are described by multiples indicators, and the most popular is the median lethal dose (LD50). At the molecular level, reversible inhibition or binding constants provide unique information on the potential activity of molecules. The important problem concerning the meaningfulness of IC50 for irreversible ligands/inhibitors is emphasized. Definitions and principles for determination of these quantitative parameters are briefly introduced in this article. Special attention is devoted to the relationships between these indicators. Finally, different approaches making it possible to link pharmacological and toxicological properties of molecules in terms of molecular interactions (or chemical reactions) with their biological targets are briefly examined. Experimental trends for future high-throughput screening of active molecules are pointed out

Enzyme Nanoreactor for In Vivo Detoxification of Organophosphates

International audienc

Tuning the Envelope Structure of Enzyme Nanoreactors for In Vivo Detoxification of Organophosphates

International audienceEncapsulated phosphotriesterase nanoreactors show their efficacy in the prophylaxis and post-exposure treatment of poisoning by paraoxon. A new enzyme nanoreactor (E-nRs) containing an evolved multiple mutant (L72C/Y97F/Y99F/W263V/I280T) of Saccharolobus solfataricus phosphotriesterase (PTE) for in vivo detoxification of organophosphorous compounds (OP) was made. A comparison of nanoreactors made of three- and di-block copolymers was carried out. Two types of morphology nanoreactors made of di-block copolymers were prepared and characterized as spherical micelles and polymersomes with sizes of 40 nm and 100 nm, respectively. The polymer concentrations were varied from 0.1 to 0.5% (w/w) and enzyme concentrations were varied from 2.5 to 12.5 μM. In vivo experiments using E-nRs of diameter 106 nm, polydispersity 0.17, zeta-potential −8.3 mV, and loading capacity 15% showed that the detoxification efficacy against paraoxon was improved: the LD50 shift was 23.7xLD50 for prophylaxis and 8xLD50 for post-exposure treatment without behavioral alteration or functional physiological changes up to one month after injection. The pharmacokinetic profiles of i.v.-injected E-nRs made of three- and di-block copolymers were similar to the profiles of the injected free enzyme, suggesting partial enzyme encapsulation. Indeed, ELISA and Western blot analyses showed that animals developed an immune response against the enzyme. However, animals that received several injections did not develop iatrogenic symptoms

Novel Bis-Ammonium Salts of Pyridoxine: Synthesis and Antimicrobial Properties

A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen’s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25–16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1–3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c12 on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c12 was considerably less toxic (LD50 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c12 (0.2%) was shown to be comparable to reference drugs efficiency on the rat’s skin model. The molecular target of 5c12 seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity