Rational design, docking, simulation, synthesis, and in vitro studies of small benzothiazole molecules as selective...

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 72 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 72 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 72 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 72 was further validated by 100 ns dynamics study. The physicochemical and pharmacokinetic (ADME) profile of compound 72 predicted it as an excellent orally bioavailable brain-penetrant molecule. To confirm these results, compound 72 was synthesized and spectrally characterized. The selectivity and inhibitory potential (IC₅₀) of compound 72 was estimated by in vitro BACE-1 and BACE-2 FRET assay. Compound 72 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).