Synthesis of Some Novel Heterocycles Bearing Thiadiazoles as Potent Anti‐inflammatory and Analgesic Agents

2‐Bromoacetyl‐3‐phenyl‐1,3,4‐thiadiazole derivative was synthesized and reacted with a number of heterocyclic amines to give a series of fused imidazole derivatives. Also, reaction of 2‐bromoacetyl‐3‐phenyl‐1,3,4‐thiadiazole with o‐phenylene diamine and 2‐aminothiophenol yielded the respective products. Moreover, reaction of 2‐bromoacetyl‐3‐phenyl‐1,3,4‐thiadiazole with thiourea, thiosemicarbazide, thiocarbahydrazide gave the respective thiazoles. The structures of all the novel products were elucidated on the basis of elemental analysis and spectral data. In addition, the biological activity of the newly synthesized compounds was evaluated, and the results obtained indicate their potency as anti‐inflammatory, analgesic, and anti‐ulcer agents. The binding mechanism of the most active compounds was studied using MOE to analyze the molecular interactions.     

Synthesis of New 1, 10‐Phenanthroline Analogs as Potent Antimicrobial Agents Using Montmorillonite K‐10 as Catalyst

A series of new 1, 10‐phenanthroline derivatives are synthesized by the four‐component domino reactions of 8‐hydroxy quinoline, aromatic aldehydes, methyl/ethyl acetoacetate and ammonium acetate in the presence of zeolite (montmorillonite K‐10) using both conventional and microwave methods. Most of the new compounds possessed moderate to significant anti‐bacterial and anti‐fungal activities.     

Synthesis of Some New Fused and Binary 1,3,4‐Thiadiazoles as Potential Antitumor and Antioxidant Agents

Annulations of 2‐amino‐1,3,4‐thiadiazole ( 1 ) with α,β‐unsaturated carbonyl compounds 2 , 5 , and 9 afforded thiadiazolo[3,2‐a]pyrimidin 3 , benzamide 7 , and bis‐pyrazole derivative 11 . Cyclization of benzamide 7 with POCl₃ gave binary imidazole derivative 8 . Moreover, alkylation of 1 with 2‐bromo‐1‐(2H‐chromen‐3‐yl) ethanone ( 9 ) followed by cyclization gave imidazo[2,1‐b]‐1,3,4‐thiadiazole derivative 15 . Multicomponent reaction of 1 with heterocyclic and/or aromatic aldehyde and thioglycolic acid afforded the corresponding thiazolidinones 17 and 19 . Finally, a one‐pot synthesis of 1 with isatin and thiosemicarbazide furnished the spirotriazole 20 . The newly synthesized compounds were evaluated as antitumor agents.     

Reaction of Hydrazonoyl Halides with Bis‐enaminones: A Convenient Route for Synthesis of Novel Polyaza‐Terheterocycles

New bis(pyrazolylenaminones) were prepared in good yields. Their synthetic utilities as precursors for regioselective synthesis of novel bis(hetarylpyrazoles) were also investigated. The mechanisms and selectivities observed in the studied reactions were discussed.     

Synthesis of Novel Aryloxy Propanoyl Thiadiazoles as Potential Antihypertensive Agents

2‐Amino‐5‐aryl/alkyl‐1,3,4‐thiadiazoles 3a‐e were synthesized from aliphatic and aromatic acids and thiosemicarbazide. These 2‐amino‐5‐aryl/alkyl‐1,3,4‐thiadiazoles 3a‐e were condensed with 2‐(naphthalenyloxymethyl) oxirane 4a‐b to prepare some naphthalenyloxy‐propanol amine derivatives 5a‐j . These compounds were synthesized as potential antihypertensive agents.     

Synthesis and Antimicrobial Activity of New Derivatives of 1,3,4‐Thiadiazoles and 1,2,4‐Triazoles with 5‐Nitroindazole as Support

The synthesis of new derivatives of 1,3,4‐thiadiazoles and 1,2,4‐triazoles was achieved using the 1,4‐disubstituted thiosemicarbazides as intermediaries.     

Utility of 2‐Acetyl Benzofuran for the Synthesis of New Heterocycles as Potential Anticancer Agents

A novel series of benzofuran derivatives containing thiazole, thiadiazine, and pyridotriazolopyrimidine were synthesized starting from 1‐(benzofuran‐2‐yl)‐3‐(1H –indol‐3‐yl)prop‐2‐en‐1‐one. Also, triazolopyrimidine derivatives were prepared from the reaction of 2‐acetylbenzofuran and pyrazole‐4‐carbaldehyde with 2‐thiobarbutyric acid and reaction of the product with hydrazonoyl halides. The structures of the newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative synthetic routes whenever possible. Anticancer activity against 60 different human tumor cell lines representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney was validated by the U.S. National Cancer Institute using a two‐stage process. The results revealed that pyrazoline‐1‐thiocarbohydrazide 4b , triazolopyrimidine 20d , and pyrimidine thione 25 have promising antitumor activity against most cell lines.     

Convenient Synthesis of Functionalized Bis‐ureidopyrimidinones Based on Thiol‐yne Reaction

The preparation of functionalized bis‐ureidopyrimidinones ( Bis‐UPy ) through the thiol‐yne reaction is described. Various Bis‐UPys with different functional groups were synthesized by using the readily available functionalized alkynes and UPy‐thiol to affirm the simplicity and versatility of the methodology.     

Chemoselective Synthesis of Enamino‐Coumarin Derivatives Identified as Potent Antitumor Agents

The reaction of 4‐aminocoumarin ( 2 ) with benzaldehyde gave the bisenamino derivatives 4 . Thus, transamination of 2 with o‐phenylenediamine furnished enamino skeleton 3 , which can be obtained from 1 . Reaction of 1 with 5‐aminoisoxazole afforded 5 . While reaction of 2 with benzalaniline, isatinanil and phenyl isothio cyanate afforded the corresponding 7 , 8 and 9 , respectively. Heterocyclic annulations of 2‐phenylthiazolidine‐4‐one 10 2‐phenylthiazolidin‐4‐one 10 and 2‐phenyl‐thiazinan‐4‐one 11 systems were achieved via reaction of 2 with benzaldehyde and rather either 2‐mercaptoacetic acid or 3‐mercaptopropanoic acid respectively. The behavior of 2 towards monochloro acetic acid and 4‐oxo‐4‐phenylbuatonic 4‐Oxo‐4‐phenylbutanoic acid was investigated. All of the newly synthesized compounds were evaluated as antitumor (cytotoxic) agents. Most of these compounds have shown significant antitumor activities.     

Synthesis of New Bis‐imidazole Derivatives

The reaction of aldimines with α‐(hydroxyimino) ketones of type 10 (1,2‐diketone monooximes) was used to prepare 2‐unsubstituted imidazole 3‐oxides 11 bearing an alkanol chain at N(1) (Scheme 2, Table 1). These products were transformed into the corresponding 2H‐imidazol‐2‐ones 13 and 2H‐imidazole‐2‐thiones 14 by treatment with Ac₂O and 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione, respectively (Scheme 3). The three‐component reaction of 10 , formaldehyde, and an alkane‐1,ω‐diamine 15 gave the bis[1H‐imidazole 3‐oxides] 16 (Scheme 4, Table 2). With Ac₂O, 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione or Raney‐Ni, the latter reacted to give the corresponding bis[2H‐imidazol‐2‐ones] 19 and 20 , bis[2H‐imidazol‐2‐thione] 21 , and bis[imidazole] 22 , respectively (Schemes 5 and 6). The structures of 11a and 16b were established by X‐ray crystallography.     

Regioselectivity in Reactions of Bis‐Hydrazonoyl Halides with Some Bifunctional Heterocycles

Bis‐hydrazonoyl chloride 1 reacts regioselectively with 3‐mercapto‐1,2,4‐triazole 2a , 2,3‐dihydro‐3‐thioxo‐1,2,4‐triazin‐5(4H)‐one 2b and 2‐mercaptobenzimidazole 2c to give the hitherto unknown annelated 2,3‐bis‐(phenylhydrazono)thiazoles 6a‐c , respectively. Reactions of 1 with the methylthio derivatives of such heterocycles afforded the annelated 3,3′‐bis‐(1,2,4‐triazoles) 11a‐c , respectively. Similar reaction of 1 with 2‐phenylamino‐4(3H)‐pyrimidinones 4 gave 2,3‐bis(phenylhydrazono)imidazo[1,2‐a]pyrimidin‐5(1H)‐ones 16 . Oxidation of 6c yielded the corresponding bis(phenylazo) derivative 15 . The regiochemistry of the studied reactions is discussed.     

Synthesis of Tetrazoloquinoline‐Based Mono‐ and Bisphosphonate Esters as Potent Anti‐Inflammatory Agents

Several new α‐alkoxy‐ and α‐hydroxyphosphonate derivatives of tetrazole‐quinolines were synthesized from the reaction of 2‐azidoquinolines 3‐carboxaldehyde 1a,b with trialkyl phosphites and dialkyl phosphites. On the other hand, azaphospholes 12a,b were obtained by treating 1a,b with tris(dimethylamino)phosphine. Furthermore, Perkin‐type condensation of 1a,b and tetraethyl methylenebisphosphonate provided the corresponding tetrazoloquinoline‐based bisphosphonate esters 14a,b . Based on the prediction results (PASS program), the anti‐inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenin‐induced paw edema in rats. Many of the new compounds exhibit considerable anti‐inflammatory properties at a dose of 50 mg/kg body weight. Especially 14a and 14b revealed remarkable activities compared with indomethacin, which was used as a reference standard in this study.     

Synthesis and Basic Coordination Properties of Side‐chain Functionalized Bis‐phosphonio‐benzophospholides

Salts containing bis‐phosphonio‐benzophospholide cations 2 a – d with an additional donor site in one of the phosphonio‐moieties were synthesized either via quaternisation of the Ph₂P moiety in the neutral phosphonio‐benzophospholide 3 , or via ring‐closure of the functionalized bis‐phosphonium ion 6 . The Ph₂P‐substituted cation 2 d formed chelate complexes [M(k²P,P′‐ 2 d )(CO)_n]⁺ with M(CO)_n = Ni(CO)₂, Fe(CO)₃, Cr(CO)₄. In the latter case, competition between formation of the chelate and a complex [Cr(kP‐ 2 d )₂(CO)₄]²⁺ was observed, and interpreted as a consequence of antagonism between the stabilizing chelate effect and destabilizing ligand–ligand repulsions. The formation of stable Pd^II and Pt^II complexes of 2 d suggests that the chelate effect may also overcome the kinetic inhibition which so far prevented isolation of complexes of these metals with bis‐phosphonio‐benzophospholides. The newly synthesized ligands and complexes were characterized by spectroscopic data, and an X‐ray crystal structure analysis of 2 a [Br]. The reactivity of chelate complexes towards Ph₃P indicates that the ring phosphorus atom is a weaker donor than the pendant Ph₂P‐group.     

Synthesis,Characterization, and Antimicrobial Properties of New 1,3,4‐Thiadiazoles Derived from Azo Dyes

Some new 1,3,4‐thiadiazoles derived from azo dyes were synthesized. Two different synthesis methods were used for these compounds: Esters pertaining to the azo dyes were converted into 1,3,4‐thiadiazoles, or benzothiazole ester derivatives were converted to 1,3,4‐thiadiazoles followed by the synthesis of azo dye derivatives. The desired products were successfully obtained using the latter method. The molecular structures of these compounds were characterized using spectroscopic methods such as FTIR, ¹H NMR, ¹³C NMR, and elemental analysis. Furthermore, antimicrobial activity was studied for the synthesized compounds. Compound 3e exhibited antimicrobial activity against three different microorganisms. Compounds 3a , 3b , and 3d had activity against two different microorganisms, while compound 3c showed activity against only one microorganism.     

An Efficient One‐Pot Synthesis of New Coumarin Derivatives as Potent Anticancer Agents under Microwave Irradiation

An efficient and rapid synthesis of coumarin derivatives was accomplished via reactions of 3‐(3‐(4‐methoxyphenyl)acryloyl)‐2H ‐chromen‐2‐one ( 3 ) with different carbon nucleophiles such as ethyl acetoacetate, ethyl cyanoacetate, malononitrile, and ethyl benzoylacetate via conventional heating and microwave irradiation conditions and were used as source of pyran and pyridine derivatives bearing coumarin moiety 4 – 11 . Compound 9a was condensed with different carbon electrophiles triethylorthoformate, phenylisothiocyanate, carbon disulfide, benzoylchloride, and acetylchloride that afforded the corresponding chromen derivatives 12 – 16 . All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of synthesized compounds were tested for in vitro cytotoxicity. The preliminary screening results showed that most of the compounds had moderate cytotoxic activity against HCT‐116 and MCF‐7 cell lines. Nevertheless, compound 10 exhibited potent activity against the two cell lines, which was comparable with the standard drug 5‐fluorouracil.     

4‐Chlorothiazole‐5‐carbaldehydes as Potent Precursors for Synthesis of Some New Pendant N‐heterocyces Endowed with Anti‐Tumor Activity

In our approach to synthesize bioactive molecules, a series of novel N‐heterocycles were synthesized and evaluated for their in vitro antitumor activity against a panel of three human cancer cell lines, namely, human breast cancer cell line (MCF‐7), human cervical cancer cell line (HeLa), and human prostate cancer PC‐3. The majority of the tested compounds exhibited significant cytotoxic activity toward the tested tumor cell lines. Analogues 33 , 34 , 31 , 38 , 21 , 23 , 22 , and 20 exhibited considerable cytotoxic activities comparable with standard drug 5‐fuorouracil. Compound 33 displayed superior cytotoxicity with IC₅₀ value of 4.12 ± 1.21 μg/mL against HeLa tumor cell line.     

Site‐ and Regioselectivity of the Reaction of Hydrazonoyl Chlorides with Perimidine Ketene Aminal. Antimicrobial Evaluation of the Products

Reaction of hydrazonoyl chlorides with perimidine ketene aminal derivative in dioxane in the presence of triethylamine afforded either pyrrolo[1,2‐a]perimidines or pyrazolyl perimidines depending on the type of hydrazonoyl chloride used. The reaction was found to be site‐ and regioselective according to the suggested mechanism. The structure of the newly synthesized compounds was established on the basis of spectral data and elemental analyses. In addition, the antimicrobial activity of the newly synthesized compounds was evaluated, and the results showed moderate activity of all compounds against the bacterial species.