Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which impaired cholinergic neurotransmission contributes to cognitive decline, and acetylcholinesterase (AChE) remains a validated target for symptomatic therapy. The indole nucleus is a privileged scaffold in medicinal chemistry, yet Mannich-type derivatives of ethyl indole-3-carboxylate have received little attention as AChE-directed agents. Five derivatives (compounds 1–5) were designed and screened in silico for drug-likeness and pharmacokinetics (SwissADME, Lipinski’s rule of five) and toxicity risk (OSIRIS Property Explorer). All five complied with Lipinski’s rule with no violations, were predicted to show high gastrointestinal absorption and blood–brain barrier permeation, and carried no mutagenic, tumorigenic or reproductive-toxicity alerts. Docking against human AChE (PDB ID: 4EY7) with PyRx/AutoDock Vina gave binding affinities of −7.1 to −10.3 kcal/mol, the best being ethyl 2-[1-(phenylamino) ethyl]-1H-indole-3-carboxylate (compound 1, −10.3 kcal/mol). The compounds were synthesized from ethyl indole-3-carboxylate, acetaldehyde and a primary or secondary amine in ethanol (yields 75–84%), recrystallized, and characterized by melting point, TLC, FT-IR, 1H NMR and mass spectrometry. In Ellman’s assay, compound 1 inhibited AChE in a concentration-dependent manner (6.76–56.41% at 0.2–1.0 µg/mL; IC50 ≈ 0.97 µg/mL. Compound 1 is a promising starting point for AChE-directed optimization; assay of the remaining derivatives, selectivity and in vivo studies are still required.