Studies on chlorophenyl, thiophenyl, and biphenyl clubbed tetrahydro bipyrazole carbaldehydes: Synthesis, antimicrobial and antioxidant activity, SAR study, in-silico pharmacokinetics, toxicity, and molecular modeling

Abstract

A library of chlorophenyl, thiophenyl, and biphenyl clubbed 3′,4,4′,5-tetrahydro-2′H-[1,3′-bipyrazole]-2′-carbaldehydes was produced via aldolic condensation followed by hetero-cyclization. Synthesized moieties were characterized by IR, ¹H, and ¹³CNMR spectral analysis. The molecular docking was conducted utilizing microbial target proteins, 1JX9, and 5C1P to explore the binding interactions of scaffolds. Analogues 4f, 4l, 4r, and 4x exhibited the best docking score of -10.3 kcal/mol with 1JX9 whereas scaffolds 4l and 4o showed maximum docking of -10.4 and -10.2 kcal/mol with target protein 5C1P. Further, scaffolds 4f, 4I, 4l, 4o, 4 u, and 4v showed excellent (pMIC: 1.92 µM/mL) antibacterial activity against S. aureus, B. subtilis, E. coli, P. aeruginosa whereas; analogues 4c, 4l, 4o, 4r, and 4v exhibited admirable (pMIC: 1.92 µM/mL) antifungal activity against R. oryzae fungal strain. Also, analogues were tested for their radical scavenging ability and 4a, 4 g, 4i, 4p, and 4x exhibited good antioxidant activity with 4i standing out as a propitious scaffold with 93.25  % radical scavenging activity. SAR study revealed that biphenyl, 4‑hydroxy-3‑methoxy phenyl, and thiophenyl moieties on the bipyrazole-carbaldehyde scaffold are accountable for virtuous antibacterial, antifungal, and antioxidant activity, respectively. Further in-silico ADME, pharmacokinetic, and toxicity properties were studied, forecasting less-toxic analogues (300 < LD₅₀ ≤ 5000). These findings collectively underscore the potential of the synthesized compounds, with 4l, 4o, 4v and 4x standing out as particularly promising candidates for further exploration.