Synthesis of new 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives with an incroporated thiazolidinone moiety and testing their possible serine protease and cercarial elastase inhibitory effects with a possible prospective to block penetration ofSchistosoma mansoni cercariae into the mice skin

Abstract

5-Substituted 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine were synthesized by interaction of 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylhydrazide with some aldehydes to give the corresponding Schiff-bases, which after cyclization gave corresponding thiazolidinones. For some of the thiazolidinones, Mannich bases reaction was carried out. All the derivatives were tested for their possible inhibitory effect on Schistosoma mansoni cercarial elastase (CE). Only, N-(4-methylbenzyledine)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonylhydrazide was found to have potent inhibitory effect on the CE activity with IC50 = 264 microM. Upon its use as a paint for mice tails before infection with S. mansoni cercariae, the compound formulated in jojoba oil caused a significant reduction (93%; P-value = 0.0002) in the worm burden. IgG & IgM in mice sera were measured by using several S. mansoni antigens by ELISA. Sera from treated infected mice (TIM) 2, 4, and 6 weeks (W) post infection (PI) showed 1.2 folds lower, 1.2 folds higher, 1.7 folds lower IgM reactivity against soluble cercarial antigenic preparation (CAP), respectively, when compared with sera collected from infected untreated mice (IUM). Sera from TIM 2, 4, and 6WPI showed 1.3, 1.6, and 1.7 folds higher IgG reactivity, respectively against CAP than the IgG reactivity from IUM. Sera from TIM 2, 4 and 6WPI showed 1.5, 1.2 folds lower and 1.4 folds higher IgM reactivity, respectively against soluble worm antigenic preparation (SWAP) when compared with sera collected from IUM. Sera from TIM 2, 4, and 6WPI showed 1.4, 1 folds lower and 1 fold higher IgG reactivity, respectivley to SWAP when compared with sera from IUM. Sera from TIM 2, 4, and 6WPI had generaly lower IgM and IgG reactivities against soluble egg antigen (SEA) when compared with sera from IUM.

New imidazolidinic bioisosters: potential candidates for antischistosomal drugs

“…However, its continuous use for more than 25 years, against infections caused by both cestodes and trematodes, has made the parasites resistant . At present, various research groups are dedicating themselves to identifying new schistosomacide agents obtained from natural (Hamed & Hetta 2005, Tallima et al 2005, Massoud et al 2005) and synthetic sources (Bahgat et al 2005, Abass & Mostafa 2005.…”

Inhibitory effect of some new uracil and thiouracil derivatives on cercarial penetration enzymes

“…Synthesis of the starting compound (1) The starting material thiouracil-5-sulfonylhdrazide (1) was prepared by reaction of thiouracil-5-sulfonylchloride with hydrazine hydrate 99 % [12].…”

“…A control group of five mice was included, whose tails were painted with the oil mixed with the solvents without the tested compound. Each mouse was infected with 80 cercariae of S. mansoni strain by tail immersion method [12].…”

“…Some efficacy of niclosamide in preventing infection by Schistosoma mansoni but not by Schistosoma haematobium was reported, but this was insufficient to warrant a recommendation for its widespread use. Penetration of cercariae into the host skin is facilitated by secretion of a potent cercarial serine protease from the preacetabular glands of cercariae [11][12][13]. Several uracil and thiouracil derivatives constitute an interesting group of compounds, many of which possess widespread pharmacological activities especially as antiviral [14], antibacterial [15], antitubercular [16], inhibition of serine protease of S. mansoni [12], antihypertensive [17], analgesic and anti-inflammatory [18], anticonvulsant [19], and anticancer agents [20].…”

“…Penetration of cercariae into the host skin is facilitated by secretion of a potent cercarial serine protease from the preacetabular glands of cercariae [11][12][13]. Several uracil and thiouracil derivatives constitute an interesting group of compounds, many of which possess widespread pharmacological activities especially as antiviral [14], antibacterial [15], antitubercular [16], inhibition of serine protease of S. mansoni [12], antihypertensive [17], analgesic and anti-inflammatory [18], anticonvulsant [19], and anticancer agents [20]. As a continuation of our previous studies on uracil and thiouracil chemistry [12,[21][22][23], the present work deals with synthesis of new compounds carrying these important nuclei in order to study their inhibitory effects on cercarial penetration enzymes to block penetration of S. mansoni cercariae into mouse skin.…”