Synthesis and structural characterization of 2-iminothiazoline/quinoline and 2-iminothiazoline/thieno[2,3-b]quinoline molecular hybrids with herbicide safening properties

Abstract

The design of molecular hybrids based on biologically active molecules is one of the most prominent strategies in modern drug design. Molecular hybridization involves combining two or more pharmacophore fragments into a single molecule, resulting in synergistic effects and combination therapy within a single multifunctional agent. These hybrids often exhibit more specific and potent activity compared to classical drugs. In this study, we developed a method for synthesizing new molecular hybrids of 2-iminothiazoline/3-cyanoquinoline and 2-iminothiazoline/3-aminothieno[2,3-b]quinoline through the reaction of N-(3-aryl-4-phenylthiazol-2(3H)-ylidene)-2-chloroacetamides with 4-aryl-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles. The starting 4-aryl-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles were synthesized by reacting aromatic aldehydes, cyanothioacetamide, and 4-(cyclohex-1-en-1-yl)morpholine. Meanwhile, the novel alkylating agents, N-(3-aryl-4-phenylthiazol-2(3H)-ylidene)-2-chloroacetamides, were prepared in 66–73 % yield via a two-step process: 1) Heterocyclization of α-thiocyanatoacetophenone with primary aromatic amines in the presence of aqueous HCl; 2) Subsequent reaction of the resulting 3-aryl-4-phenylthiazol-2(3H)-imines with chloroacetyl chloride in anhydrous benzene. The target molecular hybrids – 2-iminothiazoline/3-cyanoquinoline and 2-iminothiazoline/3-aminothieno[2,3-b]quinoline – were isolated in yields of 64–93 % and 63–92 %, respectively. The structures of the new hybrids were thoroughly characterized using X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy, including 2D NMR techniques (1Н-13С HSQC, 1Н-13С HMBC). An unusual feature in the FTIR spectra – the absence of ν(C[dbnd]O) absorption bands above 1600 cm−1 – was attributed to conjugation between the carbonyl group and either the 2-iminothiazoline C[dbnd]N fragment or the thieno[2,3-b]quinoline moiety. These findings were further supported by quantum-chemical calculations. Both computational and X-ray data indicated that the most stable conformation for 3-amino-4-aryl-N-(3-aryl-4-phenylthiazol-2(3H)-ylidene)-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamides is the s-cis conformation, stabilized by an intramolecular hydrogen bond between the NH<inf>2</inf> protons and the C[dbnd]O oxygen. Additionally, six new compounds demonstrated a noticeable antidote effect against the herbicide 2,4-D in field experiments on sunflower seedlings.