title: Synthesis of new 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives with an incorporated thiazolidinone moiety and testing their possible serine protease and cercarial elastase inhibitory effects with a possible prospective to block penetration of Schistosoma 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.
authors.affiliation: Department of Medicinal Chemistry, the National Research Center, Dokki, Cairo 12311, Egypt.
authors.forename: Mahmoud Mohamed
authors.initials: MM
authors.lastname: Bahgat
authors.forename: Amany Sayed
authors.initials: AS
authors.lastname: Maghraby
authors.forename: Mogeda Emam
authors.initials: ME
authors.lastname: Heiba
authors.forename: Andreas
authors.initials: A
authors.lastname: Ruppel
authors.forename: Omar Abd-elfattah Mohamed
authors.initials: OA
authors.lastname: Fathalla
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D051379:Mice; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D012556:Schistosomicides / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000909:Antibodies, Helminth; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011743:Pyrimidines; D012556:Schistosomicides; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase