The study report on the synthesis of a series of novel quinoxaline-alkynyl derivatives that were evaluated for their activity against Mycobacterium tuberculosis (Mtb) HR strain. A total of 19 compounds bearing an alcohol, aldehyde, mesylate and ester groups on the alkynly group, and also containing a chloro and nitro groups at the 6-position, were prepared. Seven compounds (3c, 4a-b, 5a, 5c, 6c and 6i), were found to have MIC < 10 µM, while five compounds (3b, 6a, 6b, 6d and 6h) had MIC in the range 10-20 µM. Compounds bearing a nitro substituent in the 6-position were generally more active and demonstrated a better safety profile, when compared to the unsubstituted and 6-chloro derivatives. Of the seven most active compounds, four contained nitro group at the 6-position.