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The arylhydrazones were treated with ethyl iodide, ethyl chloroacetate to afford the alkyl derivatives, which cyclized to the pyrazole derivatives, also, arylhydrazones were reacted with ethyl chlo...

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.

Polyhydrazides (PHs) and polyoxadiazoles (PODs) have broad potential applications, but PHs are generally not high-temperature resistant and PODs are commonly insoluble in organic solvents, degrade before melting, and do not show glass-transition temperature (Tg). These limitations make their processing quite difficult. To overcome these shortcomings, novel copolyhydrazides (CPHs) and copolyoxadiazoles (CPODs) based on 1,4-phenyl linkage and 1,3,4-thiadiazole moiety in the main chain have been synthesized. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed to assess the polymers thermal behavior. Also, the crystalline structure and surface morphology were examined using X-ray diffraction (XRD) and scanning electron microscopy (SEM). In addition, their solubility, viscosity, UV-visible absorption, antimicrobial characteristics were studied. Most of the new CPHs and CPODs showed high thermal stability and good solubility in polar aprotic solvents. Moreover, the CPODs melted and showed Tg and fortunately their Tg values are still high (>227 °C), so they are suitable for use under extreme conditions. It seems that incorporating 1,4-phenyl linkage and 1,3,4-thiadiazole moiety into the polymer main chain enhanced the solubility and suppressed the crystallinity, while kept the thermal stability. Furthermore, the CPODs gave large antibacterial and antifungal activities, confirming the possibility to be used in medicinal fields.

2-Aminopyridine-3-carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3, 5, 8, 11, and 14, respectively. Further annulations of 3, 5, and 8 gave the corresponding pyrido[2,3-b][1,8]naphthyridine-3-carbonitrile derivative 17, pyrido[2,3-h][1,6]naphthyridine-3-carbonitrile derivatives 18 and 19, respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4-isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a,b, 21, 22a,b, and 26, respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27. Compound 27 reacted with 4-chlorobenzaldehyde and 1H-indene-1,3(2H)-dione to give the pyridopyrimidine derivative 28 and spiro derivative 30, respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34. Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35. The structures of the newly synthesized compounds were established by elemental and spectral data.

Ethyl 5-cyano-6-mercaptonicotinate derivatives 1a,b reacted with the N-[4-(aminosulfonyl) phenyl]-2-chloroacetamide derivatives 2a,b to give the ethyl 6-[(2-{[4-(aminosulfonyl) phenyl]amino}-2-oxoethyl)thio]nicotinate derivatives 3a–d. Cyclization of 3a–d afforded the corresponding ethyl 3-amino-2-({[4-(aminosulfonyl)phenyl]amino}carbonylthieno[2,3-b] pyridine-5-carboxylate derivatives 4a–d. Ethyl 3-[4-(amino-sulfonyl)phenyl]-4-oxopyrido [3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate derivatives 5a–d and ethyl 3-[4-(amino- sulfonyl)phenyl]-4-oxopyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]-triazine-8-carboxylate derivat- ives 6a–d were prepared from 4a–d. Reaction of 1a,b with chloroacetonitrile (7) and condensation of the thus formed 3-aminothienopyridines 8a,b with dimethylformamide-dimethylacetal (DMF-DMA) yielded the corresponding ethyl 2-cyano-3-{[(N, N-dimethylamino)methylene]amino}thieno[2,3-b]pyridine-5-carboxylate derivatives 9a,b. Reaction of compounds 9a,b with the sulfadiazine (10) gave ethyl 4-{[4-...

N-1-Naphthyl-3-oxobutanamide (1) reacts with arylidinecyanothioacetamide 2a–c in ethanol/piperidine solution under reflux to yield the pyridine-2(1H)-thiones 6a–c. Compound 6a reacts with α-haloketones 7a–e to give the 6-thio-N-1-naphthyl-nicotinamides derivatives 8a–e, which cyclized to thieno[2,3-b]pyridine derivatives 9a–e. The reaction of compound 9a with hydrazine hydrate and formamide gives the thieno[2,3-b]pyridine carbohydrazide derivative 10 and pyridothienopyrimidine derivative 11, respectively. Reaction of 9a with benzoyl isothiocyanate gave thiourea derivative 12. Compound 12, upon treatment with alcoholic NaOH, gave pyridothienopyrimidine 13. Saponifications of 9a gave the amino acid 15, which affords 16 when refluxed in Ac2O. Treatment of compound 16 with AcONH4/AcOH gave 17. Diazotization and self-coupling of 9b gave the pyridothienotriazine 18. Also, diazotization of the ortho-aminohydrazide 10 give the corresponding azide 19, which was subjected to Curtius rearrangement in boiling xylene ...

The reactivity of Isothiocyanatoazobenzene 2 towards some nucleophiles was investigated. Thus, reaction of isothiocyanate 2 with aromatic amines gave thioureas 3a–d . The reaction of compound 3a with arylidenemalononitriles 4a,b afforded the corresponding 1,3-pyrimidines 7a , b . Thiosemicarbazide 8 and ethyl thiocarbamate 9 were synthesized by interaction of isothiocyanate 2 with hydrazine hydrate and ethanol, respectively. Cyclocondensation of isothiocyanate 2 with 2-aminophenol and anthranilic acid produced the novel benzoxazole 11 and quinazolinone 13 derivatives , respectively. Finally, treatment of isothiocyanatoazobenzene 2 with compounds 14 and 17 afforded the novel thioureas 15 and 18 derivatives, respectively. The structures of the synthesized compounds were established from their analytical and spectral data.

Condensation of 2-cyanomethyl-4-thiazolinone 1 with 1,3-diphenyl-pyrazole-4-carboxaldehyde 2 in ethanol containing a few drops of piperidine yielded the novel methylene derivative 3 . Compound 3 was refluxed with malononitrile to give the corresponding thiazolo[ [3] , [2] ]pyridine derivative 5 . Also, treatment of compound 3 with benzylidenemalononitriles gave the thiazolo[ [3] , [2] ]pyridine derivatives 6a–e . Refluxing of compound 6d with triethyl orthoformate furnished the ethoxymethylideneamino derivative 7 . Formic acid and malononitrile were reacted with compound 6d to produce thiazolo[ [3] , [2] ][ [1] , [8] ]naphthyridine derivative 8 and 11 , respectively. Condensation of 2 with cyanoacetohydrazide in ethanol containing piperidine as catalyst gave the hydrazone derivative 12 which, on treatment with salicyaldehyde and 2-cyano-3-(4-fluorophenyl)acrylic acid ethyl ester, yielded the novel chromene 13 and pyridinone 14 , respectively. Structures of the synthesized compounds have been esta...

The novel cyanothioformamides 2a-d were prepared by treatment of isothiocyanatosulfonamides 1a-d with potassium cyanide at room temperature. Cyclocondensation of compounds 2b,c with phenyl isocyanate as electrophile furnished the corresponding imidazolidines 3a,b. The reactivity of compound 3a towards some nitrogen nucleophiles was investigated. Thus, the thiosemicarbazone 4 and imidazo[4,5-b]quinoxaline 6 were synthesized by condensation of compound 3a with thiosemicarbazide and o-phenylenediamine, respectively. Treatment of 3a with hydrochloric acid afforded compound 7. Our investigation was extended to include the reactivity of cyanothioformamide 2 towards o-aminophenol, anthranilic acid, and o-phenylenediamine and yielded the corresponding heterocycles 9, 11 and 13 derivatives, respectively. Structures of the synthesized compounds were established by their elemental analysis and spectral data.

Cyclocondensation of cyanothioformamides (1) with arylhydrazonomalononitriles (2) afforded the novel imidazole derivatives (4a–e) in good yields. Isothiocyanatoazobenzene (6) was allowed to react with potassium cyanide and gave the new cyanothioformamide (7) which was reacted with 4-chlorophenyl isocyanate to yield imidazolidinethione (8). Compound (8) was subjected to react with hydrochloric acid, o-phenylenediamine, 4-methylaniline, and hydrogen sulfide and furnished compounds (10), (11), (12), and (15), respectively. Also, the reactivity of thiohydantoin (15) toward some electrophilic reagents such as N,N-dimethylformamide-dimethylacetal and arylidene-malononitriles was investigated. The structure of the synthesized compounds was established by analytical and spectral data. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:218–225, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20113