Synthesis, molecular modeling, and anticancer activity of new thiophene and thiophene-pyrazole analogues incorporating benzene-sulfonamide moiety as carbonic anhydrase isozymes (CA-IX and CA-XII)

•Two series of thiophene and thiophene-pyrazole analogues linked with benzene-sulfonamide moiety were synthesized.•The FMO's shape and energy were computed using the DFT/B3LYP methodology.•The in vitro anticancer activity of the synthesized analogues were tested against MCF-7, Volo and HepG2 cancer cells.•The synthesized analogues were evaluated as inhibitors of carbonic anhydrases CA-IX and CA-XII using acetazolamide reference.•The synthesized analogues were docked against the crystal construction of (PDB: 3mhc) as a representative protein for CAXII isozyme. Two series of new substituted thiophene and their corresponding thiophene-pyrazole analogues-based benzene-sulfonamide were synthesized and characterized by various spectral data. The DFT/B3LYP methodology was applied to explore the structural and energetic properties of the frontier molecular orbitals of the synthesized compounds. The geometrically optimized structure of the investigated derivatives presented a very resemble structures where the central ring, thiophene, have a planar configuration and its amine or methyl substituent was almost coplanar. Thus, the studied derivatives exhibited comparable energy gap (ΔEH-L), 1.11–2.41 eV, and may be arranged as 3b < 6b < 2b < 5b = 3a < 6a < 2a < 5a. Inspired the well-established anticancer activity of sulfonamide compounds, the newly isolated derivatives were examined against MCF-7, Volo and HepG2 cell lines, as well as, standard fibroblast cells (WI38), using Doxorubicin as reference drug. The data indicated that thiophene and thiophene-pyrazole analogues were more potent toward the VoLo cell line than the others. The 5a, 2b and 6a hybrids exhibited comparable cytotoxic effectiveness against Volo, MCF-7 and HepG2, respectively. Moreover, the inhibitory effect of the synthesized analogues on the cancer-associated carbonic anhydrases, CA-IX and CA-XII, using acetazolamide (AZA) as a reference, were explored. Both 2a and 3a displayed eminent effect on CA-IX while 6a and 6b showed good activity against the CA-XII. Additionally, the newly synthesized thiophene analogues were docked against the crystal construction of (PDB: 3mhc) as a representative protein for CA-XII isozyme. [Display omitted]