Carboxyl-Coated Nanotubes Grip Tuberculosis Drug Isoniazid, Quantum Study Shows

Tuberculosis still kills roughly two million people every year, and its first-line drug, isoniazid, is increasingly undermined by bacterial resistance that forces clinicians to raise doses and endure harsher side effects. A new computational study published in Results in Chemistry suggests a way to deliver the drug more efficiently: anchor it to the surface of a carboxyl-functionalized single-walled carbon nanotube, where quantum-chemical calculations show it binds far more strongly than it does to an unmodified nanotube. The work, led by Shahla Hamedani, Melina Shadi, and Mohadese Moradi, goes beyond the usual adsorption-energy tally and dissects the drug–carrier bond at the level of electron density, orbital interactions, and nuclear magnetic resonance signatures.

The team built a finite, hydrogen-terminated fragment of an armchair (5,5) single-walled carbon nanotube roughly 7 angstroms long, with a diameter of about 6.8 angstroms that makes the surface highly curved, and decorated one end with a carboxyl group. Using density functional theory with the M06-2X hybrid meta-GGA functional and the 6-311+G(d,p) basis set, a combination well benchmarked for hydrogen bonding and dispersion, they optimized the bare nanotube, the free isoniazid molecule, and a series of candidate adsorption complexes. Guided by the molecular electrostatic potential of isoniazid, which maps electron-rich and electron-poor regions of the drug, the researchers generated several chemically plausible starting orientations and let the optimizer decide which one nature would prefer.

The verdict was clear. Among six representative configurations, the lowest-energy arrangement bound isoniazid with an adsorption energy of −18.65 kcal per mole, or about −0.81 electron volts. That is dramatically stronger than the roughly 2 kcal per mole reported for isoniazid on pristine nanotubes, and it even edges out the 14 to 16 kcal per mole achieved with boron-doped tubes. The interaction still sits in the range associated with noncovalent adsorption, which is exactly what a drug carrier wants: strong enough to hold the payload, weak enough to release it inside a cell. Crucially, when the team repeated the optimization inside a polarizable continuum model of water, the adsorption energy softened to −13.38 kcal per mole but remained negative, meaning the complex stays thermodynamically favorable in an aqueous, body-like environment.

Thermodynamics told the same story from a different angle. At 298.15 kelvin and one atmosphere, the adsorption enthalpy was −16.65 kcal per mole in the gas phase and −12.67 kcal per mole in the implicit solvent, while the Gibbs free energy change was −7.40 and −3.39 kcal per mole respectively. Both negative enthalpies confirm the process is exothermic, and both negative free energies confirm it is spontaneous. The entropy change was negative in both environments, around −31 calories per mole kelvin, which simply reflects the loss of translational and rotational freedom when a free drug molecule locks onto a surface. Solvation barely touched the entropy term, indicating that water weakens the energetic driving force mainly by stabilizing the separated drug and nanotube rather than by changing how the complex forms.

To find out what physically holds the pair together, the researchers turned to the Quantum Theory of Atoms in Molecules, which examines the topology of the electron density between atoms. The analysis revealed two intermolecular bond paths in both the gas phase and water: one between a carboxyl oxygen on the nanotube and a hydrogen on the drug, and another between an N–H group of isoniazid and an oxygen of the nanotube’s carboxyl group. At each bond critical point, the electron density Laplacian was positive while the local energy density was negative, a signature of hydrogen bonds with partial covalent character. In other words, the drug is not just loosely clinging to the tube through vague dispersion forces; it is held by two specific, directional hydrogen bonds.

Natural Bond Orbital analysis quantified the electronic handshake behind those bonds. The dominant donor–acceptor interaction funnels electron density from the lone pair of the nanotube’s carboxyl oxygen into the antibonding σ* orbital of the drug’s N–H bond, with second-order stabilization energies of 12.78 and 7.21 kcal per mole for the two oxygen lone pairs in the gas phase. In water those values dipped to 10.50 and 6.31 kcal per mole, mirroring the weaker overall adsorption, but the same charge-transfer pathway survived. This is the classic electronic fingerprint of a hydrogen bond, and it dovetails perfectly with the QTAIM picture: adsorption proceeds by electron delocalization from the functionalized nanotube into the drug molecule.

Frontier molecular orbital analysis added a systems-level perspective. Isolated isoniazid has a generous HOMO–LUMO gap of 4.76 electron volts, but forming the complex collapses it to 1.74 electron volts in the gas phase and 1.51 electron volts in water, signaling substantially increased electronic delocalization across the drug–carrier interface. Meanwhile, the global hardness of the system rises from 0.40 electron volts for the bare nanotube to 0.87 electron volts for the complex, and electrophilicity falls from 14.54 to 7.05 electron volts, indicating that the assembled complex is electronically more stable and less eager to accept additional charge than the nanotube alone. Solvent polarization nudges these descriptors slightly, softening the complex and modestly raising its electrophilicity, but the overall electronic character established in vacuum persists in water.

Spectroscopy provided the final layer of confirmation. Gauge-including atomic orbital NMR calculations showed that the carbonyl group at the heart of the interface undergoes the largest electronic rearrangement: the isotropic shielding of the carbonyl carbon jumps from 9.77 to 24.87 parts per million upon adsorption, while the carbonyl oxygen’s shielding swings from −141.83 to 8.14 parts per million and its anisotropy plummets from 655.81 to 119.95 parts per million. The N–H group involved in the hydrogen bond also shifts, with its hydrogen’s isotropic shielding dropping from 26.39 to 21.62 parts per million. Calculated infrared spectra showed corresponding changes in C=O and N–H stretching frequencies, all consistent with a hydrogen-bonding environment reshaped by adsorption. Together, the energetic, topological, orbital, and spectroscopic lines of evidence converge on a single, coherent mechanism.

The authors are candid about the model’s limits. The calculations used a short, highly curved nanotube fragment with a single carboxyl group, so the reported energies are specific to this finite cluster rather than universal values for longer or multi-walled tubes. Chirality was not systematically varied, the conformational search was guided rather than exhaustive, and the implicit solvent cannot capture individual water molecules competing for hydrogen-bonding sites. The study is also entirely computational, awaiting experimental measurements of loading capacity, release behavior, and spectroscopic signatures. Still, the message is compelling: a simple carboxyl decoration transforms a weakly interacting carbon nanotube into a substantially stronger, thermodynamically spontaneous, water-stable carrier for isoniazid. If subsequent explicit-solvent simulations and laboratory tests bear this out, functionalized nanotubes could one day ferry higher, sustained doses of tuberculosis therapy directly to infected cells, easing the resistance problem one hydrogen bond at a time.

Subject of Research: Density functional theory investigation of isoniazid adsorption on carboxyl-functionalized (5,5) single-walled carbon nanotubes for drug delivery

Article Title: DFT investigation of the electronic structure, NMR parameters, and adsorption mechanism of isoniazid on carboxyl-functionalized (5,5) SWCNT

Article References: Hamedani, S., Shadi, M., & Moradi, M. (2026). DFT investigation of the electronic structure, NMR parameters, and adsorption mechanism of isoniazid on carboxyl-functionalized (5,5) SWCNT. Results in Chemistry, 31, Article 103916. https://doi.org/10.1016/j.rechem.2026.103916

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103916

Keywords: carbon nanotubes, isoniazid, drug delivery, DFT, hydrogen bonding, QTAIM, NBO analysis, NMR shielding, tuberculosis, nanomedicine, functionalization, computational chemistry