Work

QSAR-based drug discovery of 2-((4-Imino-3,4-dihydroquinazolin-2-yl)thio-substituted analogs targeting Mycobacterium tuberculosis

Year: 2026

Type: article

Abstract: Dihydroquinazolin-4(3 H )-imines have emerged as a promising scaffold for developing novel antimycobacterial agents. Here, we integrated QSAR modeling, in vitro screening, molecular dynamics (MD), binding free-energy calculations, and in vivo toxicity assessment to identify potent inhibitors against Mycobacterium tuberculosis ( Mtb ). Four QSAR models demonstrated strong internal and external reliability ( R 2 > 0.68; Q 2 LOO > 0.62; R 2 ext up to 0.82 ). Additional validation parameters met recommended thresholds (Q 2 -F1/F2/F3 ≥ 0.72; CCC ext ≥ 0.88 ; r 2 m aver ≥ 0.72; r 2 m delta : 0.04 ), and Williams plots confirmed that all predictions fell within the applicability domain ( h*: 0.286 ). Biological assays identified 11 active compounds, with MIC values ranging from 25 to 200 μM. Compound 2c ( p -methylphenyl derivative) and 3d ( m, p -dichlorophenyl analog) were the most potent, displaying MIC values of 50 and 25 μM, respectively. MD simulations revealed stable and specific interactions with Eis, an acetyltransferase linked to kanamycin resistance. Compound 2c exhibited a mean Δ G bind of −52.19 ± 3.21 kcal/mol, while 3d showed a more favorable Δ G bind of −73.15 ± 3.16 kcal/mol, consistent with its superior in vitro potency. Distinct interaction profiles—especially the engagement of Tyr 126 and hydrophobic clusters—help explain their differential affinities. Moreover, both leads demonstrated low to moderate in vitro cytotoxicity against HepG2 cells at the concentrations evaluated. In vivo acute toxicity in Zophobas morio indicated LD₅₀ values of 500 mg/kg for 2c and 100 mg/kg for 3d , with transient tremors and melanization observed only for 3d . Since compound 2c exhibited a safer in vivo toxicity profile, this compound was investigated for its association with antimicrobial drugs. These compounds were validated as promising anti-TB candidates, supported by robust QSAR predictivity, favorable binding energetics, and measurable in vitro and in vivo toxicity profiles, reinforcing their potentials for further optimization. • Robust QSAR models with high internal and external predictivity guided the discovery of novel dihydroquinazolin-4(3H)-imine anti-TB agents. • Integrated in silico , in vitro , and in vivo approaches identified Eis as a key molecular target for the most active compounds. • Two lead derivatives (2c and 3d) exhibited potent antimycobacterial activity and stable binding profiles supported by molecular dynamics and MM/GBSA analyses. • Distinct interaction patterns with Eis, including Tyr126 engagement and hydrophobic clustering, explain differences in binding affinity and potency. • Compound 2c displayed a favorable safety profile in vitro and in vivo , supporting its potential as a scaffold for further antitubercular optimization.

Source: Bioorganic & Medicinal Chemistry

DOI: 10.1016/j.bmc.2026.118572