Semicarbazide Derivatives Research Articles

Rapid determination of trace semicarbazide in flour products by high-performance liquid chromatography based on a nucleophilic substitution reaction.

Semicarbazide, a toxic food contaminant, widely exists in food products and it originates from the thermal degradation of a food additive of azodicarbonamide or a metabolite of nitrofurazone abused in meat specimens. Many previous methods for semicarbazide determination usually required expensive instruments, difficult-to-prepare monoclonal antibodies, and a long operation time. In this study, a high-performance liquid chromatography method was developed for the rapid determination of trace semicarbazide coupling with a nucleophilic substitution reaction firstly using 4-nitrobenzoyl chloride as derivatization reagent. The derivatization reaction was mild at room temperature for 1min in neutral solution. Then, semicarbazide derivative was separated and quantified by high-performance liquid chromatography with ultraviolet detection under optimal separation conditions at λmax = 261nm. The proposed method offered the detection limit of 1.8μg/L and was successfully applied for the rapid determination of trace semicarbazide in flour products. Semicarbazide in positive real samples could be actually found and quantified in the range of 0.47-7.53mg/kg. The recoveries were 76.6-119% with relative standard deviations of 0.5-9.1% (n = 3). This developed method was rapid, reliable, and convenient for the determination of trace semicarbazide in food.

Synthesis and anticonvulsant activity of some 1-cyclohexylidine/ cycloheptylidine-4-substitued semicarbazide derivatives

Aryl semicarbazide derivatives are reported to possess anticonvulsant activity. On the other hand unsubstituted and small substituents (less than 3 carbon atom) containing cyclohexanones prevented both pentylenetetrazole and MES induced seizures. Similarly cycloheptanone fused with benzodiazepine and furan produced anticonvulsant compounds. Therefore looking into the above facts in the present study, we have synthesized 12 derivatives of 1-cyclohexylidine/cycloheptylidine-4-substitued semicarbazide derivatives and screened them for anticonvulsant activity. The synthesis of compounds was achieved as follows: The various para substituted (H, CH3, F,Cl,Br, I) anilines were converted to aryl ureas by reacting with sodium cyanate in the presence of glacial acetic acid. These aryl ureas and aryl semicarbazides were synthesized by allowing them to react with hydrazine hydrate. Finally the aryl semicarbazides were condensed with cyclohexanone/ cycloheptanone in the presence of sodium acetate to give title compounds. All the synthesized compounds were evaluated for anticonvulsant activity by MES method using carbamazepine as standard and it was observed that all the compounds possess anticonvulsant activity comparable to carbamazepine. Carbamazepine had shown the abolition in the hind limb extensor tonic convulsion after 2 sec. whereas few compounds i.e. 1-cyclohexylidine-4-(4-fluorophenyl) semicarbazide, 1-cycloheptylidine-4-(4- fluorophenyl) semi-carbazide and 1-cycloheptylidine-4-phenylsemicarbazide were more active than standard. Overall it was found that cycloheptyl containing compounds were more active than cyclohexyl containing compounds. The unsubstitued compounds were more active than halo derivatives i.e. electron withdrawing groups, and halo compounds were more active than methyl derivatives i.e. electron donating group (CH3). The order of activity for cyclohexanone and cycloheptanone derivatives is as follows: H >F >Cl >Br >I >CH3. Among the halo derivatives, the activity decreased with increasing molecular weight of halo substituents.

Synthesis and potential anticonvulsant activity of new aryl sulfonyl semicarbazide derivatives

In the present study on the development of new anticonvulsants, twelve new aryl sulfonyl semicarbazide derivatives were synthesized and tested for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole screens. Their neurotoxicity was determined by the rotorod test. The most active compound 5i showed the MES-induced seizures with ED50 value of 7.3 mg/kg and TD50 value of 402.3 mg/kg after intraperitoneally injection to mice, which provided compound 5i with a protective index (TD50/ED50) of 55.1 in the MES test.

Synthesis and Antitumor Activity of Novel N-Benzoyl-N'-substituted Pyrimidinyl (Thio)semicarbazide Derivatives

Synthesis and Antitumor Activity of Novel N-Benzoyl-N'-substituted Pyrimidinyl (Thio)semicarbazide Derivatives

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro.

New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents.

Synthesis and in vitro cytotoxic evaluation of some novel hexahydroquinoline derivatives containing benzofuran moiety

A series of new ethyl 4-(2-(benzofuran-2-yl)-4-substituted-1,4,5,6,7,8-hexahydroquinolin-1-yl)-benzoate 3a–c was synthesized by Michael condensation of benzofuran chalcones 1a–c and cyclohexanone to give 2-(2-benzofuranyl)-4-substituted-5,6,7,8-tetrahydro-4-H -chromene 2a–c, followed by reaction of the latter with ethyl 4-aminobenzoate. Condensation of 3a–c with different amines afforded the corresponding amides 4a–e. On the other hand, upon treatment compounds 3a–c with hydrazine hydrate gave the benzohydrazide derivatives 5a–c. The reaction of compounds 5a–c with different thio/isocyanate gave the corresponding thiosemicarbazide and semicarbazide derivatives 6a–c. Meanwhile compounds 5a–c were reacted with ethyl cyanoacetate and different β-dicarbonyl compounds such as acetyl acetone, ethyl acetoacetate, and diethyl malonate to afford pyrazolyl derivatives 7a, b; 8a, b; 9a, b; and 10a–c, respectively. Moreover, 5a–c were reacted with carbon disulfide to synthesize the corresponding oxadiazolyl derivatives 11a–c, while their condensation with different aromatic aldehydes gave the corresponding Schiff bases 12a–d. Cytotoxic evaluation of some of the newly synthesized compounds against human hepatocellular carcinoma cell lines (HepG-2) revealed that the tested compounds produce promising inhibitory effect against the growth of HepG-2 cells with IC50 values ranged from 11.9 to 19.3 µg/mL.

“Turn-on” fluorescent and colorimetric determination of Cu2+ ions in aqueous media based on a Rhodamine-N-phenyl Semicarbazide derivative

We report the design and synthesis of a novel chemosensor (RGPS) rhodamine-based indicator for selective detection of Cu2+ ion. Sensing behavior toward various metal ions (M=Hg2+, Cu2+, Co2+, K+, Cs+, Ag+, Pb2+, Zn2+, Mg2+, Fe3+, Ni2+, Li+ and Al3+) was investigated by UV-Vis and fluorescence spectroscopy in acetonitrile:water (CH3CN-H2O, v/v, 9:1) solution. The indicator exhibited highly selective and sensitive colorimetric and “turn-on” fluorescent responses toward Cu2+ ions based on the ring-opening mechanism of the rhodamine spirolactam in an CH3CN-H2O (v/v, 9:1) solution. The obvious change from colorless to pale pink upon the addition of Cu2+ could make it a suitable “naked eye” indicator for Cu2+. More significantly, the sensor displayed a remarkable colorless to yellowish green fluorescence switch in the presence of Cu2+ ions. The limit of detection is proved 1.405×10−7 M from titration and 1:1 binding ratio is proved from jobs plot method. Finally, we proposed a reversible ring-opening mechanism (OFF-ON) of the rhodamine spirolactam induced by Cu2+ binding and forming a 1:1 stoichiometric complex of RGPS-Cu2+ which is supported by the material studio theory calculations.

Utility of 4-Benzylidene-2-phenyl-5(4H)-oxazolone in Synthesis of Triazine, Oxadiazole and Imidazole Derivatives of Anticipated Biological Activity

Treatment of oxazolone 1 with hydrazine hydrate at room temperature gave the (Z)‐configurated isomer hydrazide (Z)‐3 (high yield). However, refluxing 1 with hydrazine hydrate yielded the (E)‐configurated isomer hydrazide (E)‐2 (low yield).The hydrazide derivative (Z)‐3 has been utilized as synthon for the synthesis of 1,2,4‐triazinone, imidazolone, and oxadiazole derivatives through appropriate routes. The thiosemicarbazide and semicarbazide derivatives are synthesized by different routes. The structures of the new compounds were established on the basis of IR, 1H‐NMR, mass spectral data, and elemental analysis.

Novel semicarbazides and ureas of primaquine with bulky aryl or hydroxyalkyl substituents: Synthesis, cytostatic and antioxidative activity

Novel primaquine semicarbazides 7a–l and ureas 9a–g with modified benzhydryl, trityl, phenyl or hydroxyalkyl substituents were prepared and evaluated for cytostatic and antioxidative activities. Two synthetic approaches for preparation of the title semicarbazides were applied, both having certain advantages. In the first approach, the products grew from the semicarbazide side and the primaquine residue entered the molecule the last. In the second approach, semicarbazide grew from the primaquine side. This method was more convenient for synthesis of a series of semicarbazides: various products could be obtained from the same precursor N-(4-((6-methoxyquinolin-8-yl)amino)pentyl)hydrazinecarbox-amide (10). Primaquine ureas 9a–f were prepared from primaquine benzotriazolide 8 and corresponding amines and urea 9g directly from primaquine and 4-chloro-3-(fluoromethyl)phenyl isocyanate.All primaquine semicarbazide derivatives showed either prominent cytostatic activity towards all the tested cell lines (benzhydryl or trityl derivatives 7a–e) or high selectivity towards MCF-7 cells (hydroxyalkyl derivatives 7h–l), with IC50 values in the low micromolar range. The highest selectivity exerted symmetric bisprimaquine derivative 7f, with an IC50 0.2 μM against MCF-7 cells and practically no activity against other seven tested cancer cell lines. Urea derivatives 9a–f were generally less active than their semicarbazide analogues, but still selective towards MCF-7 cells. Urea 9g with the similar structure to cytostatic drug sorafenib, was the most active urea derivative.Semicarbazides 7g and 10 showed the best antioxidative activity as measured by DPPH (64% at 20 min and 90% at 60 min), while urea derivatives 9a–g, especially 9d, and semicarbazides 7a–g with lipophilic substituents exerted better LP antioxidant activity. Both semicarbazides and ureas with methoxy or chloro benzhydryl substituents and high Clog P values showed significant LOX inhibition.

Carbonic Anhydrase Inhibitors: Design, Synthesis, and Biological Evaluation of Novel Sulfonyl Semicarbazide Derivatives

A series of novel sulfonyl semicarbazides 5-13 was designed, synthesized, and evaluated for human carbonic anhydrase (hCA) inhibition. The new sulfonyl semicarbazides were tested against a panel of hCA isoforms I, II, IX, and XII, using acetazolamide (AZA, 1) as standard. All the sulfonyl semicarbazides showed subnanomolar affinity for hCA XII (pK i range 0.59-0.79 nM) and high selectivity over hCA I (58-114-fold) and hCA IX (26-114-fold) compared to hCA II (5-20-fold except 11, 121-fold). The importance of the nature of para-substitution on the sulfonyl substituted aromatic ring for potency and selectivity against one hCA isoform versus others is discussed. Overall, the research work led to the development of highly potent and selective hCA inhibitors.

Synthesis of novel 4-nitropyrrole-based semicarbazide and thiosemicarbazide hybrids with antimicrobial and anti-tubercular activity

We report the synthesis and screening of forty novel 4-nitropyrrole-semicarbazide conjugates inspired from the reported bio-potential of bromopyrrole alkaloids and semicarbazide derivatives for antimicrobial activity. Herein, hybrids 5k–5o, 5r, 5s and 5t displayed four-fold increased activity (MIC=0.39μg/mL) against Escherichia coli compared to standard ciprofloxacin. Eight hybrids, 5k–5o and 5r–5t displayed equal antibacterial activity (MIC=1.56μg/mL) against Klebsiella pneumonia compared to standard ciprofloxacin. Hybrid, 5k–5o (MIC=0.195μg/mL) displayed highly potent antibacterial activity against MSSA as compared to standard ciprofloxacin. Eight-fold superior activity was observed for four hybrids 5k–5m and 5o (MIC=0.39μg/mL) against MRSA. Further, nine hybrids displayed four-fold superior antifungal activity (MIC=0.78μg/mL) compared to standard Amphotericin B. Encouraging MICs of these hybrids recognize them as promising leads for development of potential antimicrobial drugs.

Evaluation of DNA binding with some selected hydrazide and semicarbazide derivatives.

A group of hydrazide and semicarbazide derivatives containing isopropylidene, benzylidene, cyclohexylidene, and phospholidene groups was synthesized and characterized by spectroscopic techniques. These compounds were tested for DNA interaction studies monitored by UV-Vis and IR data as well as molecular docking. Investigations on interactions of these compounds with DNA revealed an intercalative mode of binding between them. It is interesting to note that semicarbazide derivatives with aliphatic substituents showed better DNA binding than the aromatic substituents.

Synthesis and Characterization of 1,3,4-Oxadiazoles Derived From 9-Fluorenone

In the present work, 9-fluorenone-2-carboxylic acid methyl ester (1) was prepared from 9-fluorenone-2-carboxylic acid and then converted into the acid hydrazide (2). Compound (2), is the key intermediate for the synthesis of several series of new compounds such as substituted 1,3,4-oxadiazole derivatives (3-6) were synthesized from the condensation of different substituted benzoic acids with compound (2) using POCl3 as condensing agent. Treatment of compound (2) with formic acid gave the N-formyl hydrazide (7), which upon refluxing with phosphorous pentoxide in benzene yielded the corresponding 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole (8). Reaction of hydrazide (2) with phenyl isocyanate to give N-phenyl semicarbazide derivative (9), then this compound (9) convert to 5-(9-fluorenone-2-yl)-N-phenyl-1,3,4-oxadiazole-2-amine (10) via intramolecular cyclization by syrup H3PO4. Also the hydrazide (2) was treated with CS2/KOH afforded 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-thiol (11). Compound (11) was used to react with various alkyl halides and secondary amines to give 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-alkyl thiol (12-15) and 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-N-alkyl (16-19) derivatives respectively.

Synthesis and Characterization of 1,3,4-Oxadiazoles Derived From 9-Fluorenone

In the present work, 9-fluorenone-2-carboxylic acid methyl ester (1) was prepared from 9-fluorenone-2-carboxylic acid and then converted into the acid hydrazide (2). Compound (2), is the key intermediate for the synthesis of several series of new compounds such as substituted 1,3,4-oxadiazole derivatives (3-6) were synthesized from the condensation of different substituted benzoic acids with compound (2) using POCl3 as condensing agent. Treatment of compound (2) with formic acid gave the N-formyl hydrazide (7), which upon refluxing with phosphorous pentoxide in benzene yielded the corresponding 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole (8). Reaction of hydrazide (2) with phenyl isocyanate to give N-phenyl semicarbazide derivative (9), then this compound (9) convert to 5-(9-fluorenone-2-yl)-N-phenyl-1,3,4-oxadiazole-2-amine (10) via intramolecular cyclization by syrup H3PO4. Also the hydrazide (2) was treated with CS2/KOH afforded 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-thiol (11). Compound (11) was used to react with various alkyl halides and secondary amines to give 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-alkyl thiol (12-15) and 5-(9-fluorenone-2-yl)-1,3,4-oxadiazole-2-N-alkyl (16-19) derivatives respectively.

Novel 1-(4-substituted benzylidene)-4-(1-(substituted methyl)-2,3-dioxoindolin-5-yl)semicarbazide derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strain

A series of eighteen new 1-(4-substituted benzylidene)-4-(1-(substituted methyl)-2,3-dioxoindolin-5-yl)semicarbazide derivatives were designed, synthesized and characterized by spectral and elemental analyses. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) and MDR-TB strains. The activity was expressed as the minimum inhibitory concentration in μg/mL. Among the tested compounds 7j, 7m, 7o and 7q possesses equipotent activity as standard drug Isoniazid against MTB while 7m and 7q exhibited higher activity against MDR-TB strain when compared with both the reference drugs isoniazid and rifampicin. Basic structure activity relationships are presented.

ChemInform Abstract: Conventional and Microwave‐Assisted Synthesis of Pyrazole Derivatives and Screening of Their Antibacterial and Antifungal Activities.

AbstractThree series of novel quinolylpyrazole derivatives (IV), (VI) and (VIII) are synthesized by condensation reactions of propenone derivatives (III) with hydrazine or semicarbazide derivatives under conventional heating or microwave irradiation conditions.

Design and synthesis of 4-(1-(4-chlorobenzyl)-2,3-dioxoindolin-5-yl)-1-(4-substituted/unsubstituted benzylidene) semicarbazide: Novel agents with analgesic, anti-inflammatory and ulcerogenic properties

Abstract A new series of isatin semicarbazide derivatives ( 7a – 7j ) were synthesized and characterized by spectroscopic means and elemental analysis. Analgesic and anti-inflammatory screening was performed using tail-flick technique and the carrageenan-induced foot paw edema test respectively. The ulcerogenicity was also determined for all the compounds. Some of the compounds showed moderate enhancement of the activity. Among the synthesized derivatives, compound 7d showed higher analgesic, antiinflammatory and one-third of ulcer index of the reference drug.

Design, synthesis and anticonvulsant activities of novel 1-(substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives

Novel quinazolinone derivatives 5a–5n were designed, synthesized and screened for antiepileptic activity using MES and scPTZ seizures tests. Neurotoxicity study was performed by rotorod test. Compounds 5c, 5d, 5g, 5j and 5k were found active in the preliminary screening in MES model and/or scPTZ model. Further all these five compounds were administered to rats, 5c and 5d showed better activity than Phenytoin in oral route. Among all the title compounds tested, the most active one was 5c that revealed protection in MES at a dose of 30mg/kg (ip) after 0.5 and 4h. This molecule also provided protection in the scPTZ at a dose of 100mg/kg (0.5h) and 300mg/kg (4h).

Synthesis, characterization and in vitro antimicrobial activity of some 1-(substitutedbenzylidene)-4-(4-(2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)phenyl)semicarbazide derivatives

A series of 1-(substitutedbenzylidene)-4-(4-(2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl) phenyl)semicarbazide derivatives were synthesized with the aim of developing potential antimicrobials. It was characterized by FT-IR, 1H NMR, Mass spectroscopy and elemental analysis. In addition, the in vitro antibacterial and antifungal properties were tested against some human pathogenic microorganisms by employing the disc diffusion technique and agar streak dilution method. All title compounds showed activity against the entire strain of microorganisms. The relationship between the functional group variation and the biological activity of the evaluated compounds were well discussed. Based on the results obtained, compound 5j was found to be very active compared to the rest of the compounds which were subjected to antimicrobial assay.

Synthesis and Bioactivity of N-Benzoyl-N'-[5-(2'-substituted phenyl)-2-furoyl] Semicarbazide Derivatives

In order to find novel chitin synthesis inhibitors (CSIs) with good activity, benzoylphenylurea, a typical kind of CSIs, was chosen as the lead compound and 15 novel derivatives containing furan moieties were designed by converting the urea linkage of benzoylphenylureas into a semicarbazide and changing the aniline part into furoyl groups. The title compounds were synthesized by the reaction of substituted benzoyl isocyanates with 5-(substituted phenyl)-2-furoyl hydrazine, and the structures were confirmed by IR, 1H-NMR, elemental analysis and single crystal X-ray diffraction analyses (compound E2). The bioassay results indicated that the title compounds exhibit good insecticidal activity, especially towards Plutella xylostella L., but had lower fungicidal activity. Inspiringly, the title compounds possessed obvious anticancer activity against human promyelocytic leukemic cell line (HL-60), and some of the title compounds also had activity against human hepatocellular carcinoma cell line (Bel-7402), human gastric carcinoma cell line (BGC-823), and human nasopharyngeal carcinoma cell line (KB). The results indicated that the linkage in the lead compounds was important to the bioactivity and spectra. The modification on the urea linkage is an effective strategy to discover new pesticide and drug candidates.