Synthesis of Some New Folic Acid-Based Heterocycles of Anticipated Biological Activity

To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2–6a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10–15, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH(2) group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16–20a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21–24a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25–30, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi.