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A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis. Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4-nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 μM and significant molluscicidal activity, with a 50% lethal concentration (LC50) of 0.206 g/m(2). Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Context: The cryptolepines originate from the roots of the climbing shrub Cryptolepis sanguinolenta (Lindi) Schitr(Periplocaeae) which is used in Central and West Africa in traditional medicine for the treatment of malaria., Objectives: Evaluation for the first time of a series of chloro- and aminoalkylamino derivatives of neo- and norneocryptolepines for potential schistosomicidal and molluscicidal activities., Materials and Methods: A series of chloro- and aminoalkylamino substituted neo- and norneocryptolepine derivatives were synthesized. They were tested in vitro against viable Schistosoma mansoni Sambon mature worms in culturemedium with fetal serum and antibiotics and in dechlorinated water against the snail vector Biomphalaria alexandrina Ehrenberg. Active compounds were further subjected to determination of their IC50 values., Results: Results showed that six neocryptolepine and two norneocryptolepine derivatives had in vitro schistosomicidal activity on Egyptian and Puerto Rican strains of S. mansoni. The most effective derivative (2-chloro-5-methyl-N-(2-morpholin-4-ethyl)-5H-indolo[2,3b]quinoline-11-amine) has IC50 and IC90 1.26 and 4.05 μM and 3.54 and 6.83 μM with the Egyptian and Puerto Rican strains of Schistosoma, respectively. All eight derivatives showed molluscicidal activity against the vector snail B. alexandrina. The most active compound (2-chloro-11-(4-methylpiperazin-1-yl)-6H-indolo[2,3-b] quinoline) has LC50 0.6 and LC90 3.9 ppm after 24 h., Discussion and Conclusions: The findings demonstrate that introducing chloro- and aminoalkylamino side chain initiated both schistosomicidal and molluscicidal activities in these derivatives. The structure–activity relationship of this series of compounds is discussed.

An efficient synthesis of potent molluscicidal agent cyanolide A, a glycosidic 16-membered macrolide, starting from D-(-)-pantolactone is reported. Highly stereoselective aldol, oxa-Michael addition, and Yamaguchi macrolactonization are the key steps in the present synthesis.

Chalcone derivative 3 was synthesized via the base catalyzed Claisen-Schmidt condensation and was used as a precursor for synthesizing pyrazoline 11, isoxazoline 12, pyrazoline carbothioamide 13, 5,6-dihydropyrimidine-2-(1H)-thione 14 and aminopyridinecarbonitrile derivative 15. Bromination of 3 afforded the dibromo derivative 4. Monobromo derivative 5 obtained by boiling 4 in dry benzene in the presence of triethylamine. Fused thiadiazines 9a,b and 1,4-thiazine 9c derivatives were synthesized upon treatment of α-bromopropenone derivative 5 with 4-amino-4H-1,2,4-triazole-3-thiol (6) or 1-amino-2-mercapto-5-methylpyrimidin-4(1H)-one (7) or with 2-aminothiophenol (8) in ethanolic potassium hydroxide solution. The newly synthesized compounds were screened for their molluscicidal activities, whereas compounds 3, 4, 9a, 11 and 15 exhibited promising molluscicidal activities. On the other hand compounds 5, 9b, 9c, 12, 13 and 14 showed a moderate effect as compared to the standard molluscicidal agent (Bayluscide)., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

A series of fused and non fused 1,2,4-triazoles with (2,4-dichlorophenoxy) moiety are prepared utilizing 3-((2,4-dichlorophenoxy)methyl)-4-amino-4H-1,2,4-triazole-5-thiol (3). The latter on reaction with carboxylic acids, ethylchloroformate, ethylcyanoacetate and sodium nitrite gives five membered fused triazole derivatives 4a-d, 5, 6, 7 and 10, respectively. The six membered heterocycles 11, 12 and 14 are prepared by cyclization of compound 3 with phenacyl bromide, chloroacetic acid and alpha-bromoketone respectively. Most of the newly synthesized compounds were screened for their anti-inflammatory and molluscicidal activities. The compounds 4b, 4d, 11 and 14 showed potent anti-inflammatory activities in dose dependent manner while compounds 3, 4b, 8 and 10 exhibited promising molluscicidal activities., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Cascade reactions enable the rapid build-up of molecular complexity from relatively simple starting materials. Both rapid construction and the ability to prepare related structures are crucial to the study of biological activities. Here, we report an efficient, highly enantioselective and diastereoselective total synthesis of ricciocarpin A. The key feature of the synthesis is a one-pot, three-step, organocatalytic reductive Michael-Tishchenko cascade. The conciseness and flexibility of this approach not only resulted in the synthesis of the natural product, but also of its antipode and four other structural analogues. A preliminary biological evaluation of these compounds identified an analogue with significantly improved molluscicidal activity.

The toxic profile of lawsone (2-hydroxy-[1,4]naphthoquinone) and a series of [1,4]naphthoquinone derivatives was evaluated against the brine shrimp Artemia salina and against the mollusk Biomphalaria glabrata, the main transmitting vector of schistosomiasis in Brazil. Of the seventeen compounds tested nine fell below the threshold of 100 microg/mL set for potential molluscicidal activity by the World Health Organization. As a general rule derivatives with non-polar substituents presented the highest molluscicidal activities. These substances showed significant toxicity in A. salina lethality bioassay.

The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and dimedone 11a, b to afford the 4(3-indolyl)-chromene derivatives 12a, b respectively, and with the pyrazolone derivatives 13a-d to afford the arylidene exchange derivatives 14a-c and the pyranopyrazole derivative 15, respectively. The arylidene derivatives 10a, b react also with indane-1,3-dione 16 to afford the arylidene exchange derivatives 18a, b. The molluscicidal activity of the synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni, was investigated and most of them showed weak to moderate activity.

The synthesis of new furo-salicylanilides and their heterocyclic derivatives is described. Twenty-three compounds were screened for their molluscicidal activity against Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni. Five of the tested compounds showed no activity, while eighteen compounds showed strong to moderate activity using bayluscide as a reference.

2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.

2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.

A variety of bis[3-aryl-4,5-dihydro-1H-pyrazol-1-carboxaldehydes] 4a-h were obtained via reaction of bis[1-aryl-2-propen-1-ones] 3a-h with hydrazine hydrate in refluxing formic acid. In addition, the corresponding bis[1-acetyl-3-aryl-4,5-dihydro-1H-pyrazoles] 4i-m were formed through conducting the reaction of 3 with hydrazine hydrate in refluxing acetic acid. The starting bis(2-propen-1-ones) 3a-h were prepared stereoselectively as E,E'-geometric isomer via condensation of bisbenzaldehydes 1a,b with (un)substituted acetophenones 2 in ethanolic KOH solution. Anti-inflammatory as well as ulcerogenic activities of the prepared pyrazolines were evaluated in vivo and compared with that of a standard drug (indomethacin). Many of the tested compounds show remarkable anti-inflammatory properties with an ulcerogenic liability (especially 4f, g, j, and k) lower than that of the standard used drug. Compound 4f was established to be the best effectively prepared anti-inflammatory active pyrazoline derivative and safer than indomethacin with respect to its ulcerogenic liability. Molluscicidal activity of the prepared compounds against Biomphalaria alexandrina snails (the intermediate host of Schistosoma mansoni) was screened. Where, some of the prepared compounds show considerable activities.

New nitrogen derivatives from norlapachol, including four new diastereomeric 1,2,3,4-tetrahydro-1-aza-anthraquinones obtained from the Prins cyclization on suitable aminoacetaldehyde dimethylacetal derivatives with formic acid, were found to exhibit molluscicidal activity against Biomphalaria glabrata. These derivatives showed low to medium LC(50) values, similar to those reported previously for the homologous series of nitrogen derivatives of lapachol. The toxicity profile against Artemia salina was also determined for all compounds.

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4-amino-5-benzoyl-2-dicyano methyl-6-hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2-c]pyridazine and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.

Furfurylidenemalononitriles and thienylidenemalononitriles were treated with 1,3-cyclohexanediones to afford 2-amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile derivatives. The molluscicidal activity of these compounds was investigated.

The reaction of 2-hydrazino-4-(4-methoxyphenyl)-6-pheny-nicotinonitrile 3 with halo compounds yielded 4a-c,5,6. Heating 3 with carbon disulphide gave 7-(4-methoxyphenyl)-5-phenyl-3-thioxo-2,3-dihydro [1,2,4-] triazolo [4,3-a] pyridine-8-carboxylic amide 7. The behaviour of 3 towards some alpha,beta-unsaturated nitriles ,ethoxymethylene and ketene dithioacetal derivatives has been investigated, affording 9a-c,11a-c,13a-c,16a,b respectively. The activity of compounds 4a,5,6 and 7 have been investigated as molluscicidal.

[reaction: see text] Thioenoates are found to participate in highly chemoselective catalytic crossed Michael cycloisomerization with appendant aryl ketone and enoate partners to afford cyclopentene and cyclohexene products. This methodology has enabled a concise total synthesis of the potent molluscicide (+/-)-ricciocarpin A.

Some N-p-substituted phenyl uracil-5-sulphonamide derivatives have been synthesized to be evaluated as molluscicides against Biomphalanaria alexandrina snails, the intermediate host of Schistosoma mansoni. Schistosoma mansoni infected mice were treated with hemolymph obtained from pre-treated Biomphalana alexandrina snails with the products 4a, 10a, 10b and 4b or obtained from non-treated snails. The selection of the concentration based on the predetermined dose which caused mortality of less than 50% of snails/24 h. LC50 of compounds 4a, 10a, 10b and 4b was 50, 100, 200 and 50 ppm respectively. The result showed that immunostimulatory effect of treated hemolymph with compounds 4a, 10a and 4b was related to significant protective effects (44.4, 34.6 and 50.4% reduction in worm burden respectively). In addition, mean total worm burdens were significantly reduced in non treated hemolymph by 33.8%. The effect of hemolymph obtained from treated or non treated snails on S. mansoni adult worms antigens was studied by indirect immunofluorescence technique using chronic mouse sera (CMS). The results indicated that there was a strong reaction with epitopes in gut epithelium, tubercles, teigument and subtegumental musculature of untreated and treated S. mansoni adult worms antigens. Therefore, treatment of hemolymph obtained from pre-treated snails with compounds 4a, 10a, and 4b can stimulate specific immune response and induce protective effects against S. mansoni infection.

A series of benzimidazole Schiff's bases, thiosemicarbazides were synthesized, azole ring systems as 1,3,4-triazole, 1,3,4-oxadiazole were prepared. 1-Methylbenzimidazole incorporated to substituted dithio-carbamate, thiophenol, diethylamine via acetamido group were synthesized. A series of pyrimidinobenzimidazoles, triazinobenz-imidazoles, and 2-(acetonylamino)-1-methylbenzimidazole were prepared. The antimicrobial and molluscicidal activities of some newly prepared compounds were carried out.

A new series of 1,2,4-triazole derivatives and their corresponding carbamates have been synthesized and screened for their molluscicidal activity against two types of terrestrial snail, Helix aspersa and Theba pisana, by two methods of application, either as contact or as bran baits. Several of the tested compounds exhibited good molluscicidal activity, and T pisana was more sensitive than H aspersa. Substitution at the o- and/or p-positions of the phenyl ring with chlorine or bromine gave higher molluscicidal activity than the unsubstituted compound, with o,p-dichloro substitution being optimum. In addition, compounds containing two triazole moieties showed higher molluscicidal activity, particularly as stomach poisons, than the contact toxic effect of the corresponding compound with one triazole ring. In general, carbamate derivatives were more active than their corresponding 1,2,4-triazole derivatives.

A facile synthetic approach towards 3-aryl, alkyl or beta-glucopyranosyl-1,3-benzoxazin-2-ones and their thio-analogues 3 was adopted via the reaction of the easily available 3-(2-hydroxyaryl)-2-propen-1-ones 1 with a variety of isocyanates or isothiocyanates. The isolation of the open-chain carbamates 2 and then independent cyclization to the corresponding 1,3-benzoxazines 3 confirms the reaction sequence. Molluscacidal activity of the products was screened.

2-Alkoxybenzo[h]quinoline-3-carbonitriles 2 were readily synthesized via Dimroth rearrangement of 2-amino-4-aryl-5,6-dihydro-4H-naphtho[1,2-b]pyran-3-carbonitriles 5 induced by ethanolic and methanolic KOH. Compounds 2 were also obtained by the reaction of 2-arylmethylidene-3,4-dihydro-1(2H)-naphthalenones 1 with malononitrile or of ylidenemalononitriles 4 with 1,2,3,4-tetrahydro-1-naphthalenone in ethanolic and methanolic KOH. The molluscicidal activity of the products towards Biomphalaria alexandrina snails was screened.

In continuation of the previous work (Fathalla, 1992) on the synthesis of some heterocycles containing uracil moiety, we report herein the incorporation of uracil moiety into cyanopyridine thione, thiosemecarbazone, semicarbazone, cyanopyridine, aminocyano pyridine, isoxazoline, pyrazoline, pyrimidine, triazolo pyrimidine, pyran, selena and thiazole derivatives which might modify their biological activities. The biological studies revealed that the chemical compound III f showed high molluscicdal activity than other compounds. The profile of the nucleoprotein extracted from chemically (compound IIIc, e, f and g) treated or UV-irradiated B. alexandrina snails did not show appreciable differences when compared to non-treated (native) snails by using SDS-PAGE, where no obvious qualitative or quantitative differences were observed. Immunization of experimental animals with the nucleoprotein extracted from native, chemically (compound III f & g) treated or physically treated B. alexandrina snails induced significant protection against challenge with normal S. mansoni cercariae, as compared to the non-immunized challenged control. As well as, a decrease in the number of granuloma formation and the size range of granuloma was also observed in immunized animals. It is concluded that, compounds III f and g have a potent molluscicidal activity. They also induced chemical modification comparable to that induced by physical treatment in the snail's nucleoprotein, which could possibly be used in immunization against S. mansoni infection.

A facile synthetic approach towards the synthesis of 2-substituted carbamoyl (or thiocarbamoyl)-3-aryl-3,3a,4,5-tetrahydro-2 H-benz[g]indazoles 3a-r and their 2-acylating derivatives 4-6 was reported via the reaction of 2-unsubstituted-2 H-benz[g]indazoles 2 with isocyanates or their thio analogues, acid anhydrides and aliphatic or aromatic carboxylic acids. The molluscicidal activity of the products was screened.

A facile one-pot synthesis of 1-substituted carbamoyl or thiocarbamoyl-2-pyrazolines 6 is described. Also, the synthesis as well as the molluscicidal activity of 1,3,5-triaryl- (2), 1-acetyl-3,5-diaryl- (4) 2-pyrazolines are outlined.

Salicylamide amino acid conjugates were prepared utilizing 5-formyl-, 5-dicyanoethenyl-, and 5-nitroethenylsalicylic acid. 5-Substituted salicylanilides were treated with glycine and formaldehyde in a Mannich type reaction affording the corresponding 3-(N-glycino)salicylanilides. The reactions of anilines with pyrans containing the salicylyl moiety yielded the corresponding salicylanilides. The obtained compounds were tested for molluscicidal activity.

The condensation reactions of hippuric acid and its furyl derivative with salicylaldehydes or that of salicylhippuric acid analogues with furaldehyde led to the corresponding oxazoles. These were subsequently treated with hydrazine hydrate, hydroxylamine or subjected to alkaline hydrolysis to yield new o-hydroxyaryl or salicyl containing derivatives. 5-Substituted salicylanilides were treated with piperidine and formaldehyde in a Mannich type reaction affording the corresponding 3-(N-piperidinomethyl) salicylanilides. It was noticed that the presence of an electron donating group in position 3 in the salicylanilide moiety decreases the molluscicidal activity.

Thiaxanthen-9-ol (1) was condensed with nitriles 2a-e to yield the thiaxanthen-9-yl-acetonitriles 3a-e. With the thiols 7a-d, 1 yielded the thioethers 8a-d.

The alpha-methylene-gamma-butyrolactones 1-28 were tested in vitro for molluscicidal activity against Biomphalaria glabrata. The racemic compound 25 shows the best activity. The synthesis was carried out by modified Reformatzky reaction of the corresponding carbonyl compounds and bromomethylacrylic acid ethyl ester. 7-10, 17 and 22-27 have been synthesized for the first time.

Several 1-(hydroxy/substituted phenyl)propenones were tested as molluscicidal agents among which the 1-(2-hydroxy/substituted phenyl)-3-(2-furyl)propenones 1a-c show the most promising results. In an attempt to improve their activity, new dihydropyrazolo[1,5-c][1,3]benzoxazines, their thio and their dehydrogenated derivatives were prepared. The pyrazolo[1,5-c][1,3]benzoxazines 4a,b were hydrolyzed affording the 3-(2-furyl)-5-(2-hydroxy/substituted phenyl) pyrazoles 8a,b. The hydroxyimino derivatives 10a-c were synthesized together with their corresponding isoxazole derivatives 11a-c. -Molluscicidal assay indicated that the oximes 10b,c, the isoxazole 11b, the pyrazole 8b, and its N-carbamoyl derivative 9b are most effective. They have in common the conjugated system shown in Fig. 1 which is presumably the active core.

Crude extracts of seeds, leaves and barks of four Madagascan Calophyllum species: C. inophyllum, C. recedens, C. chapelieri, and C. verticullatum, have been tested for molluscicidal activity against Biomphalaria glabrata. All seed extracts showed significant activity. The major constituents of the most active Calophyllum species were examined. Some related coumarinic derivatives were synthesized in order to improve the biological activity. Among the compounds prepared, 5,7-dihydroxy-6-(2-methylbutyryl)-4-phenyl-coumarin presented an interesting molluscicidal activity.

Chemical molluscicides are useful in schistosomiasis control. A synergist can potentiate the efficacy and reduce the dosage of a molluscicide, thus decreasing the toxicity and environmental pollution. In order to search for potential molluscicidal synergists, 13 compounds of O,O-dialkyl-O-(2-substituted-3-benzofurylacetonitrile-alpha-oxi mino)phosphate or thiophosphate (VI1-13) and 2 compounds of O,O-dialkyl-O-(2-thienylacetonitrile-alpha-oximino)phosphate (X14,15) were prepared. Preliminary test demonstrated that compound X15 had strong synergic effect with sodium pentachlorophenol in combating mollusks. Compounds X14 and VI1,2,3,6,8,10,12,13, also showed some molluscicidal synergistic activity.

In order to search for potential molluscicidal synergists, eighteen O,O'-dialkyl-O''-(5-substituted-3-benzothienglyoxylonitrile oximino) phosphates and thiophosphates were synthesized. Preliminary biological screening showed that compounds I2,3,7,11,12 combined with sodium pentachlorophenate exhibited significant molluscicidal synergism against snails (Oncomelanis hupensis).

The reaction of new cinnamonitriles containing the salicylyl moiety with active methylene reagents leads to the formation of the corresponding heterocycles. Their reaction with aniline yields the corresponding salicylanilide derivatives. The obtained pyrans and anilides were tested for molluscicidal activity.

The molluscicide activity of hexanic extract from Anacardium occidentale L. (cashew) nut shell, of copper (II) complex, of lead (II) complex and anacardic acid has been compared in the laboratory in an attempt to obtain better stability than anacardic acid. This was obtained from the hexanic extract of the cashew nut shell by precipitation with lead (II) hydroxide or cupric sulfate plus sodium hydroxide or (II) cupric hydroxide followed by treatment of lead (II) complex with a diluted solution of sulfuric acid. Ten products of the mixture obtained were tested on adults snails of Biomphalaria glabrata at 1 to 10 ppm. The most active products were copper (II) complex, obtained by cupric sulfate plus sodium hydroxide, and anacardic acid (sodium hydroxide) which presented activity at 4 ppm. The anacardic acid's lead content was above the limits accepted by the United States standards.

Synthesis of some quinoline acrylamides is described. The NMR spectra of some representatives are discussed. Screening of the synthesized compounds for molluscicidal and bactericidal activity is commented.