Rational design, docking, simulation, synthesis, and <i>in vitro</i> studies of small benzothiazole molecules as selective BACE1 inhibitors

BACE-1 is an encouraging target for the development of AD therapeutics. However, many BACE-1 inhibitors failed clinical trials due to their non-selectivity towards BACE-2 or adverse effects. Herein, a set of 96 benzothiazoles were designed based on the structural features of Atabecestat and Riluzole to find a promising selective BACE-1 inhibitor. Out of the 96 designed compounds, compound <b>72</b> showed comparable binding affinity with BACE-1 as compared to Atabecestat, and more selective towards BACE-1 as compared to BACE-2. The BACE-1 docking score of Atabecestat and compound <b>72</b> were found to be –7.76 and –7.49, respectively, while their corresponding MM-GBSA ΔG_bind energy were –70.39 and –68.97 kcal/mol. In contrast, the BACE-2 docking score of Atabecestat and compound <b>72</b> were found to be –6.24 and –5.32, respectively, while their corresponding MM-GBSA ΔG_bind energy were –56.02 and –43.46 kcal/mol. The strong binding affinity of compound <b>72</b> was further validated by 100 ns dynamics study. The physicochemical and pharmacokinetic (ADME) profile of compound <b>72</b> predicted it as an excellent orally bioavailable brain-penetrant molecule. To confirm these results, compound <b>72</b> was synthesized and spectrally characterized. The selectivity and inhibitory potential (IC₅₀) of compound <b>72</b> was estimated by <i>in vitro</i> BACE-1 and BACE-2 FRET assay. Compound <b>72</b> was found to inhibit BACE-1 with IC₅₀ 121.65 nM, while it was found to be less potent on BACE-2 (IC₅₀ 480.92 nM), as compared to Atabecestat (BACE-1, IC₅₀ 13.25 nM and BACE-2, IC₅₀ 7.15 nM). The structure of Atabecestat and Riluzole was used to design benzothiazole derivatives.Compound <b>72</b> showed good binding affinity and selectivity for BACE-1 as compared to BACE-2.The affinity of compound <b>72</b> was further confirmed by a 100 ns MD simulation study.Compound <b>72</b> was predicted to be orally bioavailable and brain-penetrant.Compound <b>72</b> was found more selective BACE-1 inhibitor (IC₅₀ 121.65 nM), as compared to BACE-2 (IC₅₀ 480.92 nM). The structure of Atabecestat and Riluzole was used to design benzothiazole derivatives. Compound <b>72</b> showed good binding affinity and selectivity for BACE-1 as compared to BACE-2. The affinity of compound <b>72</b> was further confirmed by a 100 ns MD simulation study. Compound <b>72</b> was predicted to be orally bioavailable and brain-penetrant. Compound <b>72</b> was found more selective BACE-1 inhibitor (IC₅₀ 121.65 nM), as compared to BACE-2 (IC₅₀ 480.92 nM).