The foliose lichen, Parmotrema melanothrix has been chemically screened for the first time and isolated the depside atranorin (1) in significant quantity (2 %) along with methyl 2,4-dihydroxy-3,6-dimethylbenzoate (2) and methyl 3-formyl-2,4-dihydroxy-6-methylbenzoate (3). In view of its abundance, interesting structural features and significant biological profile, atranorin was subjected to chemical modification and synthesised five diverse analogues in very good yields (70~93%). The synthesised analogues along with the three isolated compounds were evaluated for their cytotoxic potential against a panel of six human cancer cell lines using MTT assay. Among the tested compounds, 1a showed enhanced activity than the parent compound (1) against almost all the tested cell lines. Significantly, 1a showed highest activity (IC50 = 15.19 μM) against prostate cancer cell line (DU145). The results indicate that complete protection of the phenolic hydroxyls in atranorin as acetates enhances the cytotoxicity, especially against DU 145.