Isoniazid-NAD truncated adducts embedding a lipophilic fragment were designed, synthesized and evaluated as inhibitors of the enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis and as antimycobacterial agents. These compounds, planned as bi-substrate inhibitors and inspired from the active metabolite of isoniazid, combine both the nicotinamide moiety of the cofactor NAD and a lipophilic hydrocarbon chain mimic of the InhA substrate. The lipophilic fragment was introduced using either Suzuki-Miyaura cross-coupling or a classical nucleophilic substitution reaction. Several compounds developed in this work were indeed able to inhibit the InhA activity and showed promising antimycobacterial activities. However a direct correlation between the expressed activity and the bi-substrate mode of action could not yet be unambiguously demonstrated.