We report the design-synthesis of several nitrothiophene containing molecules as antituberculosis agents. The molecules were designed on the basis of previously reported nitrofuran molecules in our laboratory, and the α,β-unsaturated linker was modified to cyclized linker in order to overcome the challenge of low solubility and possible toxicity. The stereo-electronic properties such as HOMO, LUMO, and  HOMO-LUMO gap along with other properties such as aqueous solvation energies and QPLogS values were studied. The designed molecules were synthesized and tested for in vitro antituberculosis activity, and some molecules were found to be highly active comparable to standard drugs. Further, the aqueous solubility was determined using visual inspection method and the designed molecules were found to be more soluble than their chalcone counterparts. Cytotoxicity studies were performed and the molecules were found to be non-cytotoxic. Electroanalytical studies proved nitro reduction as the mechanism of action for these molecules. Thus, this study provides potential nitrothiophene containing hits with improved solubility and reduced chances of toxicity.