Sobhi M. Gomha

Synthesis under microwave irradiation of [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles and other diazoles bearing indole moieties and their antimicrobial evaluation.

Microwave-assisted synthesis of some novel compounds, namely, 3-(2-methyl-1H-indol-3-yl)-6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a,b was accomplished via bromination of 2-methyl-3-[4-(arylideneamino)-5-mercapto-4H-[1,2,4]triazol-3-yl]-1H-indoles 3a,b. Also, new [1,3,4]thiadiazoles 12a,b, [1,2,4]triazoles 15a,b and [1,3,4]oxadiazoles 19a,b, with indole moieties, were prepared by cyclization of 1-[(2-methyl-1H-indole)-3-carbonyl]thiosemicarbazides 8a,b under microwave irradiation using different reaction conditions. Moreover, reaction of acid hydrazide 7 with ethyl 2-(N-phenylhydrazono)-3-oxobutanoate (20) gave the respective phenylhydrazonopyrazole derivative 21 under the reaction conditions employed. The structures of the synthesized compounds were assigned based on elemental analyses and spectral data (IR, 1H-NMR, 13C-NMR, MS). The antifungal and antibacterial activities of the new products were also evaluated.

Regioselectivity in 1,5-electrocyclization of N-[as-triazin-3-yl]nitrilimines. Synthesis of s-triazolo[4,3-b]-as-triazin-7(8H)-ones

Abstract 6-Benzyl-3-(arylmethylidenehydrazino)-as-triazin-5(4H)-ones 4 underwent regioselective cyclization upon treatment with either bromine in acetic acid containing sodium acetate or with ferric chloride in refluxing ethanol to give the respective s-triazolo[4,3-b]-as-triazin-7(8H)-ones 7 in overall good yields. The regioselectivity in the studied reactions was elucidated by comparison of 13C NMR spectra of 7 and their methyl derivatives with those of their regioisomers prepared by independent methods.

Hydrazonoyl Halides as Precursors for New Fused Heterocycles of 5α-Reductase Inhibitors

A new series of benzo[6,7]cyclohepta[1,2‐d]triazolo[4,3‐a]pyrimidines 8a–l was synthesized via reaction of heterocyclic thione 4 or its methyl derivatives 10 with hydrazonoyl halides 5a–l. Also, reaction of compound 4 with a mixture of chloroacetic acid and aromatic aldehyde derivatives gave benzo[6,7]cyclohepta[1,2‐d]thiazolo[3,2‐a]pyrimidin‐3‐ones 12–14. The microanalyses and spectral data of the synthesized compounds are in full agreement with their molecular structure. All the newly synthesized products were screened against 5α‐reductase and showed activities with good ED50 for all compounds.

Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones incorporating triazole moiety.

Reactions of hydrazonoyl halides and each of methyl 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-carbodithioate and 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazine-1-carbothioamide afforded 2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-3-phenyl-5-substituted-2,3-dihydro-1,3,4-thiadiazoles and 5-(4-substituted)diazenyl)-2-(2-(1-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazinyl)-4-arylthiazoles, respectively. Analogously, the reactions of hydrazonoyl halides with 7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-5-phenyl-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one gave 3-(4-substituted)-8-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-6-phenyl-1-arylpyrido[2,3-d]-[1,2,4]-triazolo-[4,3-a]pyrimidin-5(1H)-ones in a good yield. The structures of the newly synthesized were elucidated via elemental analysis, spectral data and alternative synthesis routes whenever possible. Twelve of the newly synthesized compounds have been evaluated for their antitumor activity against human breast carcinoma (MCF-7) and human hepatocellular carcinoma (HepG2) cell lines. Their structure activity relationships (SAR) were also studied. The 1,3,4-thiadiazole derivative 9b (IC50 = 2.94 µM) has promising antitumor activity against the human hepatocellular carcinoma cell line and the thiazole derivative 12a has promising inhibitory activity against both the human hepatocellular carcinoma cell line and the breast carcinoma cell line (IC50 = 1.19, and 3.4 µM, respectively).

Synthesis and Antimicrobial Activity of Some New Pyrazoles, Fused Pyrazolo(3,4-d)-pyrimidine and 1,2-Dihydroimidazo-(2,1-c)(1,2,4)triazin-6-one Derivatives

A novel series of 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one 6a–h, were easily prepared via reactions of novel 2-hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one (2) with hydrazonoyl halides 3a–h. In addition, we also examined the reaction of compound 2 with commercially available active methylene compounds to afford new pyrazoles containing an imidazolone moiety, expected to be biologically active. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H-NMR and mass spectral data. The antifungal and antibacterial activities of the newly synthesized compounds were evaluated.

Enaminones as Building Blocks in Heterocyclic Preparations: Synthesis of Novel Pyrazoles, Pyrazolo[3,4-d]pyridazines, Pyrazolo[1,5-a]pyrimidines, Pyrido[2,3-d]pyrimidines Linked to Imidazo[2,1-b]thiazole System

The unreported 2-[E-3-(N,N-dimethylamino)acryloyl]-3-methyl-5,6diphenylimidazo[2,1-b]thiazole 3 was prepared via the reaction of 2-acetyl-3methyl-5,6-diphenylimidazo[2,1-b]thiazole 2 with dimethylformamide dimethyl acetal (DMF-DMA). Enaminone 3 underwent regioselective 1,3-dipolar cycloaddition with nitrilimines 5a-f, to afford the corresponding pyrazoles 7a-f. The reaction of 7a,d,g with hydrazine hydrate, afforded the pyrazolo[3,4d]pyridazines 8a-c, respectively. Enaminone 3 also reacted with a hydrazines, hydroxylamine hydrochloride, 5-aminopyrazole 11, 6-aminothiouracil 15 and hippuric acid 22. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses. Enaminones are poly-dentate reagents that have been utilized extensively in this decade as building blocks in organic synthesis. Furthermore, many enaminones were found to exhibit several biological activities as antitumor, antibacterial and anticonvulsant agents. On the other hand, imidazoles possess important biological, pharmacological and therapeutic activities, where midazoles are present in compounds that have antiasthmatic, anti-inflammatory, antiulcerative, antithrombotic, fungicidal and herbicidal activities. Furthermore, some imidazo[2,1b]thiazoles were active against various cancer cell lines. Much interest has also been focused on the chemistry and anticonvulsant, analgesic, antibacterial and antisecretory activities displayed by HETEROCYCLES, Vol. 85, No. 9, 2012 2291

Novel anti-HIV-1 NNRTIs based on a pyrazolo[4,3-d]isoxazole backbone scaffold: design, synthesis and insights into the molecular basis of action

A series of novel pyrazolo[4,3-d]isoxazoles was synthesized employing the thioamide synthon 3 to obtain the phenyldiazenylthiazolyl derivatives 7a–f, the thiazolyl derivative 9, the carbohydrazonamide 12 and the triazinyl counterparts 14a–c. The prepared compounds were screened for their antiviral activities against two viral strains of HIV-1 (RF and IIIB). All the compounds exhibited a highly potent antiviral capacity, having submicromolar to subnanomolar EC50 values with all derivatives being more active against the tested HIV strains than the reference drug efavirenz. The therapeutic index of these novel pyrazoloisoxazoles was also evaluated against the host cells CEM-SS or MT-4 and they exhibited a high therapeutic window. To further investigate the molecular basis of their actions, the inhibitory ability of these compounds was bioscreened against the HIV-1 viral enzyme reverse transcriptase (RT). The observed very potent inhibitory power of the pyrazolo[4,3-d]isoxazoles against RT prompted a molecular docking study to try exploring the potential binding modes of these compounds with their respective molecular targets. Finally, in vitro exploration of the metabolic stability of this series of compounds was evaluated by employing a rat-plasma half-life assay and they demonstrated reasonable hydrolytic resistance.

3-Amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H- chromeno (2,3-d )pyrimidine: An Effecient Key Precursor for Novel Synthesis of Some Interesting Triazines and Triazepines as Potential Anti-Tumor Agents

A number of interesting heterocycles were prepared through interaction of the intermediate 3-amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno-[2,3-d]pyrimidine (1) and reagents such as hydrazonyl halides 2 to furnish triazine derivatives 4a–l. Reaction of 1 with phenacyl bromide afforded compound 5. Moreover, the title compound 1 was subjected to condensation with active methylene compounds (ethyl acetoacetate and ethyl benzoylacetate) to give triazipinones 8a,b. The condensation with aromatic aldehydes afforded either the triazole derivatives 10a–d or Schiff base 11. In addition, the behaviour of compound 1 towards activated unsaturated compounds namely dimethyl acetylene dicarboxylate and ethoxymethylenemalonitrile was studied and it was found to furnish the triazine 13 and triazepine derivative 15, respectively. Combination of title compound 1 with chlorinated active methylene compounds delivered the triazine derivatives 18a–c. Reaction of 1 with chloroacetonitrile furnished compound 20. The structures of the products were elucidated based on their microanalyses and spectroscopic data. Finally, the antitumor activity of the new compounds 4a and 8a against human breast cell MCF-7 line and liver carcinoma cell line HepG2 were recorded.

Diphenylpyrroles: Novel p53 activators.

Cellular tumor antigen p53 is crucial for cancer prevention via different mechanisms. E3 ubiquitin-protein ligase HDM2 binds to p53, blocks its ability to activate transcription, and therefore acts as a negative regulator. Blocking p53 binding site on HDM2 was believed to generate efficient antitumor agents. So far, limited scaffolds were reported with HDM2 antagonist activity. Herein, diphenylpyrroles were introduced and evaluated as a novel scaffold in the field of p53 activators. An efficient synthesis of novel 3-heteroaryl-pyrroles is described via reactions of E-3-(dimethylamino)-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)prop-2-en-1-one or E-1-(2-methyl-4,5-diphenyl-1H-pyrrol-3-yl)-3-morpholinoprop-2-en-1-one with hydrazine hydrate, phenyl hydrazine, hydroxylamine, various heterocyclic amines and active methylene compounds.

One Pot Single Step Synthesis and Biological Evaluation of Some Novel Bis(1,3,4-thiadiazole) Derivatives as Potential Cytotoxic Agents

A novel series of bis(1,3,4-thiadiazole) derivatives were synthesized in one step methodology with good yields by condensation reaction between bis-hydrazonoyl chloride 1 and various reagents. The structures of the prepared compounds were confirmed by spectral data (IR, NMR, and MS), and elemental analysis. The anticancer activity against human breast carcinoma (MCF-7) cancer cell lines was evaluated in MTT assay. The results revealed that the bis-thiadiazole derivatives 5c,d, 7b,c and 9c had higher antitumor activity than the standard drug Imatinib.