Integrated structural and supramolecular analysis combined with biological and computational studies of two indole-DMPP hybrids as potential antituberculosis agents.
ARTURO, Richard Fernando D'Vries; CUENU-CABEZAS, Fernando; BAENA, Alejandro Martínez; ARANAGA, Carlos Andrés; ALÍ-TORRES, Jorge; ORJUELA, Adrian L.; ELLENA, Javier; CORTES-GONZALEZ, Edwar.
ARTURO, Richard Fernando D'Vries; CUENU-CABEZAS, Fernando; BAENA, Alejandro Martínez; ARANAGA, Carlos Andrés; ALÍ-TORRES, Jorge; ORJUELA, Adrian L.; ELLENA, Javier; CORTES-GONZALEZ, Edwar.
Abstract: This work reports the synthesis, structural elucidation, supramolecular analysis, antimicrobial evaluation, molecular docking and DFT analysis of two novel indole-dimethylpyrazolopyrimidine hybrids, namely 2-(1-hexyl-1H-indol-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine (Hexa) and 5,7-dimethyl-2-(1-octyl-1H-indol-3-yl)pyrazolo[1,5-a]pyrimidine (Octa). Single-crystal X-ray diffraction revealed that both compounds crystallize in the monoclinic P21/n space group with one molecule per asymmetric unit and closely related unit-cell parameters. Supramolecular organization is mainly governed by weak C-H···N heterosyntons together with dominant H···H van der Waals interactions, as evidenced by Hirshfeld surface and fingerprint plot analyses, contributing approximately 20% and 60% of intermolecular contacts, respectively. Biological assays demonstrated selective antimycobacterial activity for Octa, exhibiting MIC values of 128 µg/mL against Mycobacterium chelonae, M. fortuitum, and M. smegmatis, 256 µg/mL against M. abscessus, and a notably enhanced activity of 16 µg/mL against Mycobacterium tuberculosis. Density functional theory calculations and molecular docking studies supported these findings, revealing stronger binding affinity of Octa toward essential M. tuberculosis targets through stabilizing hydrophobic contacts and p-stacking interactions. The combined experimental and theoretical results establish a clear relationship between structural modification, electronic properties, and biological recognition, highlighting indole-DMPP hybrids as promising scaffolds for further structure-guided development of antitubercular agents.
@article={003299843,author = {ARTURO, Richard Fernando D'Vries; CUENU-CABEZAS, Fernando; BAENA, Alejandro Martínez; ARANAGA, Carlos Andrés; ALÍ-TORRES, Jorge; ORJUELA, Adrian L.; ELLENA, Javier; CORTES-GONZALEZ, Edwar.},title={Integrated structural and supramolecular analysis combined with biological and computational studies of two indole-DMPP hybrids as potential antituberculosis agents},journal={Journal of Molecular Structure},note={v. 1367, p. 146130-1-146130-8 + supplementary materials},year={2026}}