Herein, we report the synthesis and anti-tubercular studies of novel molecules based on thiophene scaffold. We identified two novel small molecules 4a and 4b, which demonstrated 2-fold higher in vitro activity (MIC: 0.195 μM) compared to first line TB drug, isoniazid (0.39 μM). The identified leads demonstrated additive effect with front line TB drugs (isoniazid, rifampicin and levofloxacin) and synergistic effect with a recently FDA-approved drug, bedaquiline. Mechanistic studies (i) negated the role of Pks13 and (ii) suggested the involvement of KatG in the anti-tubercular activity of these identified leads.