Discovery of novel theophylline derivatives bearing tetrazole scaffold for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit for AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of AChE and BACE1. In particular, the potential inhibitory of these compounds was rapidly and accurately estimated via knowledge-methods. The in vitro tests were then performed to validate the artificial intelligent approach. Among these, compound 12 exhibited the most potent AChE inhibition with an IC₅₀ of 15.68 μM, while showing limited activity against BACE1. In addition, six compounds were indicated that are able to inhibit AChE, however, the theophylline derivatives play poor performance over the BACE1 target. Atomistic simulations were finally applied to clarify the ligand-binding mechanism to the biological target. The outcomes disclose that theophylline derivatives rigidly form van der Waals interactions to AChE via π-stacking and SC contacts. Overall, the theophylline derivatives may offer a potential scaffold for novel anti-AD agents.

Fig. 1. (A) Structure of theophylline compound as an AChE inhibitor; (B) structure of tetrazol compound as an AChE inhibitor; (C) design targeted compounds.

Scheme 1. General procedure for synthesis final compounds 11–27. Reagents and conditions: (a) ClCH₂CN, K₂CO₃, KI, acetone, 60 °C, 4 h; (b) (i) NaN₃, ZnCl₂, DMSO, 120 °C, 2 h; (ii) halogenide-ester derivatives, DMSO, 90 °C, 12 h; (c) (i) NaOH, MeOH, rt, 2 h; (ii) HCl to pH = 2–3; (d) aniline/phenol derivatives, EDC·HCl, DMAP, HOBt, DCM, DMF, rt to 50 °C, 12 h.

Fig. 2. FELs of six complexes AChE + compounds over equilibrium conformations via PCA approach during interval 100–200 ns of MD simulations. In particular, (A–F) patterns are FEL of compounds 12, 15, 18, 22, 25, and 26, respectively.

Fig. 3. Two-dimension ligand-binding poses of AChE – theophylline derivatives matching to the minima a, a′, b, c, c′, d, d′, e and f. The diagram were generated via the Maestro free version.