Restructuring Antiviral Quinazolinone Frameworks to Derive and Optimize Inhibitors of Chikungunya Virus

Chikungunya virus (CHIKV) results in debilitating chronic pain in nearly half of those infected. With no FDA approved small molecule-based therapeutics available, we screened compounds to reveal quinazolinone (<i>S</i>)-<b>1a</b> with a modest 0.3 log reduction of CHIKV titer and no significant toxicity (CC₅₀ > 40 μM). Five scaffold regions were surveyed to improve the titer reduction efficiency. Chemistry was established to preserve the enantiopurity of 2-piperidinyl-containing analogues, affording (<i>R</i>)-<b>1h</b> (BDGR-651) which reduced CHIKV titer in normal human dermal fibroblasts by 4.1 log at 10 μM (EC₅₀ = 0.86 μM). Excellent solubility and mouse microsomal and plasma stabilities were observed, and confocal microscopy of infected Vero E6 cells treated with (<i>R</i>)-<b>1h</b> showed a dose-dependent protective effect. A narrow selectivity index prevented <i>in vivo</i> evaluation, but the study showed that antiencephalitic alphavirus quinazolinones could be reengineered to inhibit CHIKV, an arthritogenic virus, against which previous analogues showed no significant activity.