Antimicrobial Activity and DFT Studies of a Novel Set of Spiropyrrolidines Tethered with Thiochroman-4-one/Chroman-4-one Scaffolds

Abstract

A novel series of 14 spiropyrrolidines bearing thiochroman-4-one/chroman-4-one, and oxindole/acenaphthylene-1,2-dione moieties were synthesized and characterized by spectroscopic techniques, as well as by three X-ray diffraction studies, corroborating the stereochemistry. Quantum chemical calculations studies, using the DFT approach, were performed to rationalize the stereochemical outcome. These N-heterocycles were evaluated for their antibacterial and antifungal activities against some pathogenic organisms. Several compounds displayed moderate to excellent activity towards the screened microbe strains in the study compared to Amoxicillin (AMX), Ampicillin (AMP), and Amphotericin B. Furthermore, a structural activity relationship (SAR) was established considering the synthesized compounds. Pharmacokinetic studies reveal that these derivatives exhibit an acceptable predictive ADMET profile (Absorption, Distribution, Metabolism, Excretion and Toxicity) and good drug-likeness.

Keywords: DFT; [3+2] cycloaddition; chroman-4-one; crystal structure; spiropyrrolidine; thiochroman-4-one.

Figure 1

(A) Biologically relevant thiochroman, thiochromanone, and chromanone derivatives, (C) Biologically relevant spiropyrrolidines bearing oxindole or acenaphthylene-1(2H)-one moieties, and (B) Our target compounds.

Scheme 1

Synthesis scheme for the target compounds 4 and 9.

Figure 2

¹H (black) and ¹³C {¹H} NMR (green) chemical shifts (ppm) of the selected compound 4a (see also Figure S3 in the Supporting Material).

Figure 3

¹H (black) and ¹³C {¹H} NMR (green) chemical shifts (ppm) of the selected compound 9c (see also Figure S20 in the Supporting Material).

Figure 4

Ball and sticks presentation of the molecular structure of 4a recorded at 100 K. Only one of the two independent molecules is shown. Apart from stereochemically relevant H atoms, all other hydrogen atoms are omitted for clarity. Furthermore, an EtOH molecule of crystallization, present in the asymmetric unit, is not depicted.

Figure 5

Ball and sticks presentation of the molecular structure of 4e recorded at 100 K. Only stereochemically relevant H atoms are shown.

Figure 6

Ball and sticks presentation of the molecular structure of 9c recorded at 100 K. Only one of the two independent molecules is shown. Apart from stereochemically relevant H atoms, all other hydrogen atoms are omitted for clarity.

Scheme 2

Proposed mechanism for the regio- and stereoisomeric 1,3-dipolar cycloaddition reaction of dipolarophile 1d with azomethine ylide d_3.

Figure 7

Molecular electrostatic potential (MEP) formed by mapping of the total density over the electrostatic potential for compounds 4a, 4e, 4c, 9d, 9e, and 9f.