Aim: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. Materials & Methods: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aβ42 and tau aggregation, of antioxidant activity, and of brain permeation. Results: Using, as a template, a lead rhein–huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Aβ42 and tau antiaggregating and antioxidant activities. Conclusion: Second-generation naphthyridine- and thienopyridine-based rhein–huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.