Synthesis and Structure-Activity Relationship of Some New Thiophene-Based Heterocycles as Potential Antimicrobial Agents.

Several new pyrazole, pyridine, [1,2,4]triazolo[1,5-α]pyrimidine, benzimidazo[1,2-a]pyrimidine and 1,2,4-triazolo[3,4-c][1,2,4]triazine derivatives incorporating a thiophene moiety were synthesized from (E)-ethyl 5-(3-(dimethylamino)acryloyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate (1). The structures of the newly synthesized compounds were confirmed by IR, ¹H-, (13)C-NMR, mass spectral data and elemental analysis. The antibacterial and antifungal activities of all the synthesized compounds were evaluated. The results indicated that compounds 9, 12, and 19 were found to be more potent than the standard drug Amphotericin B against Aspergillus fumigates. Additionally, compound 12 exhibited higher activity than the standard drug Amphotericin B against Syncephalastrum racemosum.

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses.

Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6-8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, ¹H-(13)C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn't guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.

(E)-Ethyl 2-anilino-5-[3-(dimethyl-amino)-acrylo-yl]-4-phenyl-thio-phene-3-carboxyl-ate.

In the title compound, C24H24N2O3S, the phenyl rings form dihedral angles of 55.65 (11) and 79.60 (11)° with the plane of the thio-phene ring. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond, generating an S(6) ring motif. In the crystal, centrosymmetrically related mol-ecules are linked into dimers by two pairs of C-H⋯O inter-actions.

Ethyl 4-acetyl-5-anilino-3-methyl-thio-phene-2-carboxyl-ate.

In the title compound, C16H17NO3S, a thio-phene derivative with amino phenyl, acetyl, methyl and ethyl carboxyl susbtituents attached to a central thio-phene ring, the phenyl and thio-phene rings form a dihedral angle of 36.92 (9) Å. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond, which forms an S(6) ring motif.