Novel furo[3′,2′:6,7]chromeno[4,3-c]pyrazoles: Synthetic approaches, Spectral Characterization, DFT, insilico and Biological studies

The electron deficient 5-chlorofurochromene-6-carbonitrile 3 was utilized as key substrate to construct a novel series furo[3′,2′:6,7]chromeno[4,3-c]pyrazoles. Treatment of substrate 3 with S-methyldithiocarbazte, thiosemicarbazide, 7‑chloro-4-hydrazinoquinoline and 3-hydrazino-5,6-diphenyl-1,2,4-triazine afforded the corresponding furochromenopyrazole derivatives 4, 5, 8 and 9. The newly prepared compounds presented good antimicrobial efficiency due to the formation substituted pyrazoles annulated furochromonenes at face c. Also, the synthesized compounds showed varied cytotoxicity against HepG-2 cell lines (IC50 ranged between 8.17- 26.57 µM); where compound 9 exhibited the highest activity. Additionally, an exhaustive theoretical study using DFT techniques explored the reactivity profile of the current molecules at the B3LYP/6-311G++(d,p) level. Global reactivity descriptors, HOMO-LUMO energies, and frontier molecular orbitals (FMO) were all included in this investigation. Compound 9 has the highest softness while compound 3 has the most electrophilicity index (ω) and electronegativity value (χ). MEP map and local descriptors in the form of Fukui functions of the precursor 3 were employed to analyze the reactive sites for nucleophilic and electrophilic attack. Compound 3 has greater positive fk+ and Δfk values at sites C26 (CN) and C7 (CCl) and therefore stronger electrophilic characteristics. Consequently, nucleophilic assaults started at C26 (CN) and then at C7 (CCl). The 1H and 13C NMR chemical shifts were computed by GIAO approximation, where the computed and experimental NMR measurements produced consistent findings. Further, the calculated first hyperpolarizability of the synthesized compounds is higher than urea, therefore, excellent heterocycles for applications as non-linear optics. The compounds' drug-likeness properties were established by determining their ADME characteristics.