A communicable disease such as tuberculosis (TB), which takes ∼10 million lives worldwide every year, is one of the major concerns for future generations. The intake of multiple antibiotics is increasing because of the emergence of multiple drug-resistant TB (MDR-TB) to pathogens which do not respond to the first-line TB drugs. Even though numerous drugs are available on the market, there is a huge need for MDR-TB drugs. Herein, our emphasis was to synthesise a series of 2,4,6-substituted quinoline conjugated piperazine coupled sulfonamides, as well as amides, and to study and evaluate their <i>in vitro</i> antibacterial activity against both susceptible and resistant pathogens of Gram-positive and Gram-negative bacteria. Furthermore, their antituberculosis activity was assessed against non-virulent, virulent and MDR pathogens. Few compounds displayed inhibitory activity against bacterial growth, but two compounds displayed significant inhibitory activity against all the TB strains (lowest MIC of 10g is 0.07 μM and 11e is 1.1 μM), which are more effective than other 1st line and 2nd line TB drugs. These two compounds are less cytotoxic, and could be developed as antibiotics or MDR-TB drugs by improving their hydrophilicity.