Synthesis, X-Ray, Spectral Characterization, DFT, and Molecular Docking Calculations of 2-(5-Nitro-1-H-Indazol-1-yl) Acetic Acid

In this work, theoretical and experimental studies of a new Indazole derivative named 2-(5-nitro-1-H-indazol-1-yl) acetic acid (3), including the synthesis and characterization by ¹H and ¹³C-NMR, FT-IR, UV spectroscopies are reported together with its X-ray crystal structure. The compound crystallizes in the monoclinic crystal system of P21/c space group and unit cell constants: a = 7.8541(10) Å, b = 7.9274(11) Å, c = 15.877(2) Å, β = 101.149(5)°. In the crystal, O–H···N and C–H···O hydrogen bonds form a 3-D network structure containing small channels running parallel to the b-axis. B3LYP/6-311++G** calculations in the gas phase and ethanol solution suggest the existence of C1 and C2 conformers where the structure of C1 in both media is in agreement with that observed by X-ray diffraction. Probably, the high values observed in the dipole moments of C1 justify its presence in gas and solution phases. The stabilities of both forms were justified by NBO and AIM calculations where C1 is more stable than C2. C1 shows a higher solvation energy, dipole moment, and higher hydration than C2 while the frontier orbitals suggest a higher reactivity of C1 over C2. Force fields and complete vibrational assignments were performed for the C1 conformer because it was detected in the solid phase. Scaled force constants for both forms are also reported. Calculated chemical shifts for (3) are consistent with the experimental ¹H and ¹³C-NMR spectra in the DMSO-d₆ solution. The anti-COVID activity of 3 is investigated by its molecular docking into the binding site of SARS CoV-2 3CLpro (3 C-like protease). It shows a moderate binding affinity into the binding site of 3 C-like protease with a maximum binding energy of −5.57 kcal mol⁻¹.