Lymphatic filariasis (LF) is one of the World Health Organization's top 10 neglected tropical diseases, primarily caused by Brugia malayi. B. malayi asparaginyl-tRNA synthetase (BmAsnRS) is considered an excellent antifilarial target due to its high expression in parasites, structural differences from human aminoacyl-tRNA synthetases, and the availability of a high-throughput screening platform. To discover drug leads targeting BmAsnRS, we previously screened ~73,000 extracts from 36,720 microbial strains and identified active strains. Here we report the bioassay-guided dereplication of another active strain, Streptomyces sp. 4875, leading to the discovery of four alkylresorcinols named adipostatin A (1), adipostatin B (2), adipostatin C (3), and adipostatin D (4). All four adipostatins inhibit BmAsnRS with apparent IC50 values of 15 μM (for 1, 2, 3) and 30 μM (for 4). They efficiently kill adult B. malayi parasites in vitro: at 100 μM, 2 and 3 kill all worms within 24 h, while 1 and 4 require 48 h; at 100 nM, 1 and 3 achieve complete killing in 9 and 8 days, respectively. Importantly, none of the adipostatins exhibit significant cytotoxicity to human HepG2 cells at concentrations up to 100 μM. The adipostatins, previously unrecognized for use in LF treatment, represent another lead scaffold for antifilarial drug discovery.