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

AbstractIn 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.Keywords: 5-nitro-1H-indazoleX-rayDFTvibrational studymolecular docking AcknowledgmentsThis work is supported by grants from CIUNT Project N° 26/D608 (Consejo de Investigaciones, Universidad Nacional de Tucumán). The authors would like to thank Prof. Tom Sundius for his permission to use MOLVIB. The support of NSF-MRI Grant #1228232 for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory is gratefully acknowledged.Authors contributionsMohamed El Hafi: Performed experiments and calculations, analyzed the data Methodology, data curation, review & editing, Mohammed Boulhaoua: Performed experiments and calculations, analyzed the data. Sanae Lahmidi and Nadeem Abad: Analyzed the data Methodology, data curation, Lhoussaine El Ghayati: Methodology, review & editing, Joel T. Mague: X-ray diffraction analysis, review & editing, María V. Castillo: Conceptualization; Methodology; Data curation, Silvia Antonia Brandán: Validation; Visualization; Writing - original draft; Writing; review & editing, El Mokhtar Essassi: Conceptualization, methodology, supervision, review & editing.Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThis study is supported via funding from Prince Sattam bin Abdulaziz University project number (PSAU/2023/R/1444).