The present invention is directed to antifolate compounds having the structure wherein: X is CHR.sub.9 or NR.sub.9; Y.sub.1, Y.sub.2, and Y.sub.3 independently are O or S; V.sub.1 and V.sub.2 independently are O, S, or NZ; Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R.sub.1 and R.sub.2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R.sub.3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, --C(O)-alkyl, --C(O)-alkenyl, or --C(O)--alkynyl; as well as pharmaceutically acceptable esters, amides, salts, solvates, and prodrugs thereof. The compounds are useful in pharmaceutical compositions and in methods of treating multiple conditions, including abnormal cell proliferation, inflammatory diseases, asthma, and arthritis.