Nitro based DprE1 inhibitors exemplified by benzothiazinones have been reported to elicit potent anti-tubercular activity. Poor PK properties associated with benzothiazinones have inspired the discovery of alternative nitro based DprE1 inhibitors. Quinolone based antibiotics on the other hand have good PK properties. The potent anti-tubercular activity of nitro compounds and the good PK properties of the quinolones have elicited an interest in us to construct a new class of nitro containing compounds around the quinolone scaffold with the aim of identifying novel DprE1 inhibitors with potent anti-tubercular activity. Thus, we report herein the anti-tubercular activity of novel 6-nitroquinolone-3-carboxamide derivatives achieved using less than five cheap synthetic transformations. Among the 23 target compounds evaluated for anti-tubercular activity, 12 were active against Mtb─ exhibiting activity in the range of <0.244-31.865 μM. Compound 25 having a molecular weight of 399 Da and ClogP value of 2.7 is the most active (MIC: <0.244 μM) in this series. The SAR analyses suggest that anti-tubercular activity was influenced by substituents at position N-1 (R) and C-3 (R) of the quinolone ring. The activity data suggest that the nature of R has a stronger influence on the SAR compared to R; with a fluorobenzyl and chlorobenzyl moiety at R being the most favoured when R is an aliphatic amine. Docking study confirms that compound 25 binds to the same hydrophobic pocket as does TCA1, and other nitro based DprE1 inhibitors, with its nitro group in close proximity with Cys387 residue.