Wagnat W. Wardakhan

Heterocyclizations of pregnenolone: Novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3-b]pyridine derivatives and their cytotoxicity evaluations

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with 4-phenyl-3-thiosemicarbazide gave the thiosemicarbazone derivative 3. The latter compound underwent heterocyclization reactions to give the thiazolyl hydrazonoandrostane and pyrazolyl semicarbazidoandrostane derivatives 5a-d, and 9a-d, respectively. On the other hand compound 1 reacted with either malononitrile or ethyl cyanoacetate to give the Knoevenagel condensated products 11a and 11b, respectively. Compounds 11a,b afforded the thiophenyl pregnane derivatives 12a and 12b, respectively, their reactivity toward some chemical reagents was studied. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference drug, doxorubicin.

The Knoevenagel reaction of cyanoacetylhydrazine with pregnenolone: Synthesis of thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole, pyran and pyridine derivatives with anti-inflammatory and anti-ulcer activities.

The reaction of pregnenolone with cyanoacetylhydrazine and ammonium acetate at 120°C gave the Knoevenagel condensation product 3. The latter reacted with different reagents to give thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole and pyran derivatives. The anti-inflammatory and anti-ulcer evaluations of the newly synthesized products were evaluated and the results showed that compounds 4, 8c, 10, 11, 13c, 15a, 15c, 17a, 17b, 17e, 18a and 18f possessed higher activity compared to the rest of the compounds. In addition to this, the toxicity of these active compounds was studied against shrimp larvae where compounds 15a, 15c and 18a showed non-toxicity against the tested organisms.

Synthesis of Polyfunctionally Substituted Thiophene, Thieno[2,3-b]pyridine and Thieno[2,3-d]pyrimidine Derivatives

The thiophne derivatives 4a–c were prepared according to the Gewald procedure. Their reactivity towards a variety of chemical reagents was studied to give thienopyridines and pyrimidines. Biological investigations were carried on the newly synthesized products.

Studies on 2-Aminothiophenes: Synthesis, Transformations, and Biological Evaluation of Functionally-Substituted Thiophenes and Their Fused Derivatives

Abstract Heterocyclic enamines1 reacted with ethyl acetoacetate to afford the corresponding amide derivatives2. Treatment of2 with carbon disulphide yielded the dipotassium salts3which reacted in-situ with a variety of α -haloketones to give the respective substituted thiophenes5,8, and13. The reactivity of the latter products towards various chemical reagents was studied to yield their fused thiophene derivatives7,10,12, and14, respectively. Some representative compounds were tested for antimicrobial activity.

Reaction of 3-phenyl-5-aminopyrazole with carbon disulfide: A novel synthesis of 3-(3′-phenylpyrazol-5′-yl)-4-phenylpyrazol-2-thione as well as of pyrazolo[3,4-d]thiazole and pyrano[2,3-d]thiazole derivatives

Summary3-Phenyl-5-aminopyrazole (1) reacts with carbon disulfide, followed byin situ reaction with α-haloketones3a–c, to afford5,7a, and7b, respectively. Compounds5 and7 were further utilized for the formation of heterocycles and their fused derivatives.Zusammenfassung3-Phenyl-5-aminopyrazol (1) reagiert mit Schwefelkohlenstoff und anschließendin situ mit den α-Halogenketonen3a–c zu5,7a und7b. Die Verbindungen5 und7 wurden weiter zu Heterocyclen und ihren kondensierten Derivaten umgesetzt.

Utility of 2-Aminothiophene-3-carboxamide in the Synthesis of Biologically Active, Fused Heterocyclic Derivatives

Abstract 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1) reacted with 3-iminobutyronitrile (2) to give the imino product 3. The latter product was used in synthesis of a series of annulated products which have pharmaceutical interest. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria was studied.

HETEROCYCLIC SYNTHESIS WITH ISOTHIOCYANATE AND SULFUR: A NOVEL ROUTE FOR THE SYNTHESIS OF PYRIDINO[2,3-d]THIAZOLE, THIAZOLO[4′,5′:2,3] PYRIDINO[4,3-d]PYRIDAZINE AND THIAZOLO[4,5-b]ISOQUINOLINE DERIVATIVES

Abstract The reaction of phenyl isothiocyanate and sulfur with the Knovenagel condensated adducts la-e afforded the pyridino[2,3-d]thiazole derivatives 3a-e. The latter compounds proved to be versatile starting materials for the synthesis of polyfunctionally substituted thiazolo[4′,5′:2,3]pyridino[4,3-d]pyridazine and thiazolo[4,5-b)isoquinoline derivatives. Chemical and spectroscopic evidence for the structures of the new compounds, along with a sequence leading to their formation is described.

Synthesis of pyridine, pyran and thiazole containing thiophene derivatives and their anti-tumor evaluations

The multi-component reaction of 2-acetylthiophene with aromatic aldehydes and either malononitrile or ethyl cyanoacetate gave the pyran derivatives 4a–4f and pyridine derivatives 5a–5f. On the other hand, the reaction of the 2-acetylthiophene with elemental sulfur and either malononitrile or ethyl cyanoacetate gave the thiophene derivatives 6a and 6b; respectively. Compounds 6a and 6b underwent a series of heterocyclic reactions to give thiazole and thiophene derivatives. All the products were assessed for antitumor activity towards human cancer human gastric cancer (NUGC and HR), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), human breast cancer (MCF), nasopharyngeal carcinoma (HONE1) cell lines. Compounds 4e, 4f, 5e, 5f, 7b, 8b, 10e, 10f, 11e, 11f, 14d-f, 15d-f, 16a,b and 18b exhibited optimal cytotoxic effect against cancer cell lines, with IC50’s in the nM range. Moreover, 7b, 10e, 14d, 15e and 16b showed no toxicity against shrimp larvae. Anti-proliferative cell activity against cancer cell lines of the most potent compounds showed that compounds 5f and 10e achieved the highest activities among the tested compounds.

Synthesis and cytotoxicity of fused thiophene and pyrazole derivatives derived from 2-N-acetyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

The reaction of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with chloroacetyl chloride gave the 2-chloroacetamido derivative 3. The latter reacted with hydrazine hydrate to give the hydrazine derivative 5 which was used to form the hydrazone derivatives 7a, b and 9a, b via its reaction with some carbonyl compounds. Moreover, it produced the pyrazole derivatives 11a, b through its reaction with either acetylacetone or ethyl acetoacetate. On the other hand, compounds 5 and 3 were used to form some thiazole, pyridine, and fused derivatives. The cytotoxicity of the newly obtained products was evaluated against some of the human cancer and normal cell lines where the results showed that compounds 3, 11b, 13, 18c, 18d, 21, 23, and 24 exhibited optimal cytotoxic effect against cancer cell lines, with IC50’s in the nM range.

Reaction of Ethyl 2-Diazo-4,5,6,7-Tetrahydrobenzo[B] Thiophene 3-Carboxylate with Benzoyl Acetonitrile: Synthesis of Pyrazoles, Pyridazines, Pyrimidines and Their Fused Derivatives

Abstract The reaction of ethyl 2-diazo-4,5,6,7-tetrahydrobenzo[b]thiophene 3-carboxylate I with benzoylacetonitrile (2) gave compound 3. The reactivity of the latter product towards variety of chemical reagents was studied to give fused thiophene derivatives of high potential pharmaceutical uses.