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Both 2‐(N‐arylcarbamoyl)methylsulfanyl‐3‐cyano‐5‐ethoxycarbonyl‐6‐methyl‐4‐(2′‐thienyl)pyridines 2a‐e and their isomers, 3‐amino‐2‐(N‐arylcarbamoyl)‐5‐ethoxy‐carbonyl‐6‐methyl‐4‐(2′‐thienyl)thieno[2,3‐b]pyridines 3a‐e were synthesized by reaction of ethyl 3‐cyano‐1,2‐dihydro‐6‐methyl‐4‐(2′‐thienyl)‐2‐thioxopyridine‐5‐carboxylate (1) with the respective N‐aryl‐2‐chloroacetamides in the presence of different basic catalysts. Compounds 3a‐e were used as precursors for synthesizing of pyridothienopyrimidinones 4a‐e, pyridothienotriazinones 5a‐e and tetrahydropyridothienopyrimidinones 6a‐c via treatment with triethyl orthoformate, nitrous acid, and/or 4‐chlorobenzaldehyde respectively. The photophysical properties of aminothienylthienopyridines 3a‐e and tetrahydropyridothieno‐pyrimidine‐4(3H)‐ones 6a‐c were studied and the fluorescence data revealed that all selected compounds possess AIE behaviors in solution and in solid state. Most of the prepared compounds were evaluated in vitro for their antibacterial and antifungal activities, and considerable results were obtained. Moreover, the cytotoxic activity of thienopyridines 3a‐d against MCF‐7 and HepG2 cell lines was evaluated and they showed moderate to very strong activity. [ABSTRACT FROM AUTHOR]

3‐Cyano‐5‐ethoxycarbonyl‐6‐methyl‐4‐(2′‐thienyl)‐pyridine‐2(1H)‐thione (1) is synthesized and reacted with chloroacetamide or chloroacetonitrile to give 3‐amino‐5‐ethoxycarbonyl‐6‐methyl‐4(2′‐thienyl)‐thieno[2,3‐b]pyridine‐2‐carboxamide 3a or its 2‐carbonitrile analog 3b, respectively. Cyclocondensation of 3a with triethylorthoformate produced the corresponding pyridothienopyrimidineone 4, which on heating with phosphorus oxychloride gave 4‐chloropyrimidine derivative 5. Compound 5 was used as key intermediate for synthesizing compounds 6, 9, 10, 11, and 12 upon treatment with some nucleophilic reagents such as thiourea, 5‐phenyl‐s‐triazole‐3(1H)‐thione, piperidine, morpholine, or hydrazine hydrate, respectively. Reaction of pyridothienopyrimidinethione 6 with N‐(4‐tolyl)‐2‐chloroacetamide or ethyl bromoacetate afforded the corresponding S‐substituted methylsulfanylpyrimidines 7 or 8. The condensation of 3b with triethylorthoformate gave azomethine derivative 13, which was reacted with hydrazine hydrate to give ethyl 3‐amino‐3,4‐dihydro‐4‐imino‐7‐methyl‐9‐(2′‐thienyl)pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐8‐carboxylate (14). Compounds 12 and 14 were used as precursors for synthesizing other new thienylpyridothienopyrimidines as well as isomeric thienyl‐s‐triazolopyridothieno‐ pyrimidines. All synthesized compounds were characterized by elemental and spectral analyses such as IR, 1H NMR, and 13C NMR. In addition, majority of synthesized compounds were tested for their antifungal activity against five strains of fungi. Moreover, compounds 3a, 5, 6, 8, and 22 were screened for their anticancer activity against HEPG‐2 and MCF‐7 cell lines. [ABSTRACT FROM AUTHOR]

Ethyl 5-cyano-1,6-dihydro-2-methyl-4-(2'-thienyl)-6-thioxonicotinate ( A ) was synthesized and reacted with ethyl chloroacetate in the presence of sodium acetate or sodium carbonate to give ethyl 5-cyano-6-((2-ethoxy-2-oxoethyl)thio)-2-methyl-4-(2'-thienyl)nicotinate ( 1a ) or its isomeric thieno[2,3- b ]pyridine 2a . 3-Aminothieno[2,3- b ]pyridine-2-carboxamide 2b was also synthesized by the reaction of A with 2-chloroacetamide. The reaction of 1a with hydrazine hydrate in boiling ethanol gave acethydrazide 3 . Heating ester 1a with hydrazine hydrate under neat conditions afforded 3-amino-1 H -pyrazolo[3,4- b ]pyridine 10 . Compounds 2b , 3, and 10 were used as precursors for synthesizing other new thieno[2,3- b ]pyridines and pyrazolo[3,4- b ]pyridines containing mainly the ethyl nicotinate scaffold. Structures of all new compounds were confirmed by elemental and spectral analyses. Most of the obtained compounds were evaluated for their insecticidal activity toward the nymphs and adults of Aphis gossypii (Glover,1887). Some compounds such as 4 , 9b, and 9c showed promising results. The effect of some sublethal concentrations, less than LC 50 , of compounds 4 , 9b, and 9c on the examined Aphis was subjected to a further study. The results demonstrated that exposure of A. gossypii nymphs to sublethal concentrations of compounds 4 , 9b, and 9c had noticeable effects on their biological parameters, i.e., nymphal instar duration, generation time, and adult longevity. The highest concentration C1 of all three compounds increased the nymphal instar duration and generation time and decreased adult longevity and vice versa.

Ethyl-2-((8-cyano-3,5,9a-trimethyl-1-(4-oxo-4,5-dihydrothiazol-2-yl)-4-phenyl-3a,4,9,9a-tetrahydro-1 H -pyrazolo[3,4- g ]isoquinolin-7-yl)thio)acetate ( 5 ) was synthesized, and its structure was characterized by IR, MS, and NMR ( 1 H and 13 C) and verified by a single-crystal X-ray structure determination. Compound 5 adopts a "pincer" conformation. In the crystal, the hydrogen bonds of -H···O, C-H···O, and O-H···S form thick layers of molecules that are parallel to (101). The layers are linked by C-H···π(ring) interactions. The Hirshfeld surface analysis shows that intermolecular hydrogen bonding plays a more important role than both intramolecular hydrogen bonding and π···π stacking in the crystal. The intramolecular noncovalent interactions in 5 were studied by QTAIM, NCI, and DFT-NBO calculations. Based on structural activity relationship studies, leucine-rich repeat kinase 2 (LRRK2) was found to bind 5 and was further subjected to molecular docking studies, molecular dynamics, and ADMET analysis to probe potential drug candidacy., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The reaction of ethyl 5-cyano-2-methyl-4-(thiophen-2-yl)-6-thioxo-1,6-dihydropyridine-3-carboxylate ( 1 ) with 2-chloroacetamide or its N -aryl derivatives gave ethyl 6-((2-amino-2-oxoethyl)thio)-5-cyano-2-methyl-4-(thiophen-2-yl) nicotinate ( 2a ) or its N -aryl derivatives 2b - f , respectively. Cyclization of 2a - f into their isomers 3a - f was carried out by heating in absolute ethanol in the presence of a catalytic amount of sodium ethoxide. The o -aminoamide 3a was reacted with some aryl aldehydes in refluxing ethanol containing a few drops of conc. HCl to afford the corresponding tetrahydropyrimidinones 4a - d . The cyclocondensation reaction of 3a with some cycloalkanones such as cyclopentanone and cyclohexanone gave the corresponding spiro compounds 5a,b. The crystal structures of compounds 2a and 2d were determined by single-crystal X-ray diffraction techniques. All new compounds were evaluated for their insecticidal activity toward nymphs and adults of Aphis gossypi .