Unorthodox synthesis, biological activity and DFT studies of novel and multifunctionalized naphthoxocine derivatives

Abstract

A new promising protocol has been developed for the synthesis of scarce oxocine derivatives 3a-e and 6 through addition of amine-based nucleophiles such as hydroxylamine hydrochloride, primary amine and hydrazide to chromonylidene benzothiazol-2-ylacetonitrile 2 in refluxing dioxane under metal free reaction conditions in moderate to good yields. Other nitrogen nucleophiles such as piperidine, hydrazine and thiosemicarbazide failed to afford the corresponding oxocinols, and instead pyridine derivatives 7, 8 and 10 were obtained exclusively. Predictive study for the biological activities using PASS (prediction of activity spectra for biologically active substances) online software showed optimistic activities for oxocinols 3a-e in the treatment of cancer, influenza A and microbial infections. Additionally, DFT studies of oxocine derivatives 3a-e and 6 indicated the presence of required thermodynamics parameters for the application in dye-sensitized solar cells (DSSCs).

Fig. 1. Representative examples of biologically active oxocine natural products.

Scheme 1. Synthesis and energy-optimized geometrical structures of E- and Z-chromonylidene 2.

Scheme 2. Working hypothesis.

Scheme 3. Reaction of chromonylidene 2 with different 1° amines.

Scheme 4. Reaction of chromonylidene 2 with cyanoacetic acid hydrazide.

Scheme 5. Reaction of chromonylidene 2 with piperidine.

Scheme 6. Reaction of chromonylidene 2 with hydrazine hydrate.

Scheme 7. Reaction of chromonylidene 2 with thiosemicarbazide.

Fig. 2. Electron densities on OH and NH functionalities of the key intermediate B in case of products 3a, 8 and 10.

Fig. 3. Energy level diagram of oxocine derivatives 3a–e and 6.

Fig. 4. Simulated absorption spectra of oxocine derivatives 3a–e and 6.