The effects of ortho-/meta-/para-anilinyl (C6H6N) substituted onto the amino phenyl ring along with the presence of an additional methyl (CH3) substituent on the 2-amino group of the 1,4-naphthoquinone core were investigated in modified compound series 8. The para-aniline compound 8 (pIC50 -0.279) exerted more potent activity than did the meta-compound 8b (pIC50 -0.390), which could be due to the alteration of the mass descriptor, H8m (8 = 0.021, 8b = 0.002, Table S1). Furthermore, remarkable enhancement effects were observed when the methyl group was introduced into the 2-amino position of both the para- (8a, pIC50 0.259) and meta- (8c, pIC50 0.123) aniline compounds, among which 8a was shown to be the most potent compound. The markedly increased activity of N-methyl-substituted compounds 8a and 8c may be governed by the mass descriptor, as indicated by the 0.49-fold and 0.33-fold decreases in their Mor04m values compared with those of non-substituted N-methyl compounds 8 and 8b, respectively. Likewise, the effects of ortho-/meta-/para-carboxyl (COOH) and acetyl (COCH3) substitutions on the amino phenyl ring were investigated in modified compound series 5, 6, and 7 (detailed discussion is provided in Supplementary information).