In the present investigation, 4-nitroacetophenone, on condensation with appropriate aldehydes in ethanolic sodium hydroxide solution, yielded the corresponding chalcones. These corresponding chalcones were reacted with hydrazine hydrate, urea, thiourea, and hydroxylamine hydrochloride, which led to the formation of corresponding novel pyrazole, pyrimidine, and isooxazole derivatives, respectively. All newly synthesized compounds were evaluated for their antimycobacterial activities against Mycobacterium tuberculosis using agar dilution. The results indicated that most of the compounds demonstrated better in vitro antitubercular activity, and the compound 1g has a MIC of 1.56 lg mL-1 . QSAR analysis revealed that molecular descriptors mean electrotopological state (Ms) and average valance connectivity index chi-0 (0 vAv) contributed positively while 3-path Kier alpha-modified shape index (3 ja) contributed negatively. The objective of our study is to generate new leads and to optimize their structure to display the potent efficacy.