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Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (<b>3a</b>)- and azaindole–piperazine (<b>3b</b>)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (<b>1</b>). Notably, <b>3a</b> displayed considerably stronger enzyme inhibitory activity and cellular potency than did <b>3b</b> and <b>1</b>. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in <b>3b</b> and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, <b>3b</b> had a lower binding affinity score than did <b>3a</b> and <b>1</b>, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of <b>3a</b> from that of <b>3b</b> in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.