Several studies have demonstrated the cytotoxic potential of nor-beta-lapachone derivative against cancer cells. Considering nor-beta-lapachone as an important prototype, a set of new 3-substituted nor-beta-lapachones was synthesized by a new synthetic route that involves the use of synthetic intermediate generated for coupling with several nucleophiles containing the carbohydrate and 2H-pyrazole substituent moieties. All the compounds were screened against four tumor cell lines. Two of the compounds showed moderate cytotoxicity, while the other compounds strongly inhibit all tested cancer cell lines.