Background: Cutaneous Leishmaniasis (CL) remains a major public health concern in endemic regions, where access to safe, effective, and affordable oral therapies is limited. Although chloroquine and azithromycin have been proposed as alternative treatments to conventional antimonials, differences in their therapeutic performance and underlying molecular behavior remain insufficiently understood.

Objective: To compare the clinical efficacy of oral Chloroquine and Azithromycin in CutaneousLeishmaniasis and to rationalize treatment outcomes through density functional theory (DFT)–based electronic structure analysis.

Methods: A randomized controlled trial was conducted between December 2025 and February 2026 at the Dermatology Department, Pakistan Institute of Medical Sciences (PIMS), Islamabad. Sixty patients with parasitologically confirmed cutaneous leishmaniasis (CL) were randomly allocated to one of two treatment groups. Patients received either oral chloroquine or oral azithromycin according to their age and body weight. Adults (≥18 years) were treated with oral chloroquine (250 mg twice daily) or oral azithromycin (250 mg twice daily), whereas pediatric patients (<18 years) received weight-adjusted doses of chloroquine (10 mg/kg/day in two divided doses) or azithromycin (10 mg/kg on day 1, followed by 5 mg/kg/day on days 2–5, or according to the institutional treatment protocol), without exceeding the recommended adult dose. Treatment was continued for six weeks. Clinical response was evaluated fortnightly based on lesion size reduction, induration, and complete epithelialization, with parasitological clearance confirmed by rebiopsy. In parallel, DFT calculations were performed using the B3LYP/6-311++G(d,p) level of theory to compute frontier molecular orbitals and global reactivity descriptors for both drugs.

Results: Clinically, chloroquine demonstrated significantly higher efficacy (90%) compared to azithromycin (60%) (p = 0.015), with consistent performance across age groups, sex, and lesion locations, particularly in extremity lesions and shorter disease duration. DFT analysis revealed that chloroquine possesses a smaller HOMO–LUMO energy gap (4.083 eV), lower global hardness, higher softness, and a markedly greater electrophilicity index than azithromycin. In contrast, azithromycin exhibited a wider energy gap (4.845 eV), higher hardness, and lower electron affinity, indicating greater electronic stability but reduced chemical reactivity. Molecular electrostatic potential analysis further showed more favorable charge delocalization in chloroquine, supporting stronger intermolecular and charge-transfer interactions.

Conclusion: The superior clinical efficacy of chloroquine in cutaneous leishmaniasis is strongly supported by its electronic and reactivity characteristics derived from DFT calculations. Azithromycin, while structurally stable and moderately effective, exhibits lower chemical reactivity due to its larger HOMO–LUMO gap, reduced electrophilicity, and dispersed electronic density. These findings establish a clear molecular basis for the observed clinical outcomes and highlight the value of integrating computational chemistry with clinical evaluation in antileishmanial drug assessment.