A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness factors to explore a new chemical space. The synthesised chemical library, consisting of fused-bridged dodecahydro-2<i>a</i>,6-epoxyazepino[3,4,5-<i>c</i>,<i>d</i>]indole skeletons, followed lead likeness factors in terms of molecular weight, C-sp<sup>3</sup> fraction and Clog <i>P</i>. Screening of the 25 compounds against lung cells infected with SARS-CoV-2 led to the identification of 2 hits. Although the chemical library showed cytotoxicity, the two hits (3b, 9e) showed the highest antiviral activity (EC<sub>50</sub> values of 3.7 and 1.4 μM, respectively) with an acceptable cytotoxicity difference. Computational analysis based on docking and molecular dynamics simulations against main protein targets in SARS-CoV-2 (main protease M<sup>pro</sup>, nucleocapsid phosphoprotein, non-structural protein nsp10-nsp16 complex and RBD/ACE2 complex) were performed. The computational analysis proposed the possible binding targets to be either M<sup>pro</sup> or the nsp10-nsp16 complex. Biological assays were performed to confirm this proposition. A cell-based assay for M<sup>pro</sup> protease activity using a reverse-nanoluciferase (Rev-Nluc) reporter confirmed that 3b targets M<sup>pro</sup>. These results open the way towards further hit-to-lead optimisations.