Salicylanilide Inhibitors of Toxoplasma gondii

Abstract

Toxoplasma gondii(T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose anti-apicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.

In silico design of anti-atherogenic biomaterials

“…We have previously employed several different approaches to construct QSAR models of biological activities of drugs and biomaterials [35–38]. QSAR models associate variations in the chemical structure of the subject materials, as encoded by molecular descriptors, with variations in their corresponding biological activity (e.g., inhibition of oxLDL uptake).…”

Salicylanilide diethyl phosphates as cholinesterases inhibitors

“…Surprisingly, salicylanilide diethyl phosphates 1-27 showed significantly weaker inhibition of AChE than their sulphur isosters, salicylanilide diethyl thiophosphates (phosphorothioates). For BChE, the average activity was higher in the case of thiophosphates, but six phosphates (19,20,22,24,25, and 26) exhibited lower IC 50 values than all thiophosphates [22].…”

“…Pursuant the procedure described in [29], the determination was performed subsequently: The reaction mixture containing phosphate buffer, AChE or BChE and chosen salicylanilide derivative (in one of the chosen concentrations) was prepared and intensively stirred. In given times (5,10,15,20,30,40, 50, 60, 80, 240 and 1380 min), DTNB and ATCh were added to the sample withdrawn from reaction mixture, quickly mixed and absorbance was measured. Consequently the enzyme activity was determined.…”

“…Salicylanilide-like derivatives have exhibited a wide range of interesting biological activities [14][15][16][17][18][19][20]. Previously, two groups of salicylanilide derivatives have been reported as cholinesterases inhibitors -salicylanilide N-alkyl carbamates [21] and, more importantly, O,O-diethyl thiophosphates (phosphorothioates) which were described as potent inhibitors of both AChE and BChE with IC 50 values in the micromolar range [22].…”

“…All tested compounds 1-27 showed greater inhibition of AChE than rivastigmine but not galantamine, and six of them(19,20,22,(24)(25)(26) inhibited BChE more effectively than both drugs.Members of Group 2 (5-chloro derivatives synthesized from 4-chlorosalicylic acid) are more effective inhibitors of BChE (IC 50 s form 0.9 to 11.5 lM) than derivatives of Group 1 (10.3-68.3 lM).…”