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[Display omitted] • A series of cyclopropylamine containing cyanopyrimidine derivatives were synthesized and evaluated for anticancer activity. • VIIb, VIIi and VIIm were also found to be nontoxic against normal cells (cell line HEK-293), with an IC 50 value of more than 50 µM. • LSD1 inhibition assay revealed IC 50 values for VIIb, VIIi and VIIm as 2.25, 1.80 and 6.08 µM. In this series we report the structure-based design, synthesis and anticancer activity evaluation of a series of eighteen cyclopropylamine containing cyanopyrimidine derivatives. The computational predictions of ADMET properties revealed appropriate aqueous solubility, high GI absorption, no BBB permeability, no Lipinski rule violations, medium total clearance and no mutagenic, tumorigenic, irritant and reproductive toxic risks for most of the compounds. Compounds VIIb, VIIi and VIIm emerged as the most potent anticancer agents among all compounds evaluated against 60 cancer cell lines through the one-dose (10 µM) sulforhodamine B assay. Further, the multiple dose cell viability studies against cancer cell lines MOLT-4, A549 and HCT-116 revealed results consistent with the one-dose assay, besides sparing normal cell line HEK-293. The three potent compounds also displayed potent LSD1 inhibitory activity with IC 50 values of 2.25, 1.80 and 6.08 µM. The n -propyl-thio/isopropyl-thio group bonded to the pyrimidine ring and unsubstituted/ electron donating group (at the para - position) attached to the phenyl ring resulted in enhanced anticancer activity. However, against leukemia cancer, the electron donating isopropyl group remarkably enhanced anti-cancer activity. Our findings provide important leads, which merit further optimization to result in better cancer therapeutics. [ABSTRACT FROM AUTHOR]