Synthesis and in vitro evaluation of substituted pyrimido[5,4-d]pyrimidines as a novel class of Antimycobacterium tuberculosis agents

Abstract Novel pyrimido[5,4- d ]pyrimidines were efficiently synthesized and evaluated for antibacterial activity against Mycobacterium tuberculosis strain H 37 Rv. This new structural class of compounds showed high activity against the bacilli. The activity depends on the substituents present in N-3 and C-8 of the pyrimido[5,4- d ]pyrimidine core. Compounds having a 4-MeOC 6 H 4 , a Ph or a 4-FC 6 H 4 group as the substituent on C-8 and a 4′-pyridinyl, a Ph or 2′-furyl group as the substituent on N-3 were active. The highest activity was registered for compounds having 4-FC 6 H 4 or 4-MeOC 6 H 4 as substituents in C-8 and a heteroaryl group as substituent in N-3. The new compounds showed high potency and promising antitubercular activity, as is the case of N -[8-[(4-fluorophenyl)amino]-4-iminopyrimido[5,4-d]pyrimidin-3(4H)-yl]isonicotinamide with an IC 90  = 3.58 μg/mL, and should be regarded as new hits for further development as a novel class of Antimycobacterium tuberculosis agents.