The discovery of HpFabZ inhibitors is now of special interest in the treatment of various gastric diseases.
In this work, three series of derivatives (compounds 3, 4, and 5) were designed, synthesized, and their
biological activities were investigated as potential HpFabZ inhibitors in a two phased manner. First, we
designed and synthesized two series of derivatives (3a-r and 4a-u) and evaluated the enzyme-based assay
against HpFabZ. Five compounds (3i-k, 3m, and 3q) showed potential inhibitory activity, with IC50 values
less than 2 μM. Second, a focused combinatorial library containing 280 molecules was designed employing
the LD1.0 program. Twelve compounds (5a-l) were selected and synthesized. The activity of the most
potent compound 5h (IC50 ) 0.86 μM) was 46 times higher than that of the hit 1. The high hit rate and the
potency of the new HpFabZ inhibitors demonstrated the efficiency of the strategy for the focused library
design and virtual screening.