CoMFA-SIMCA model for antichagasic nitrofurazone derivatives

The physico-chemical properties of some 5-nitro-2-furaldehyde semicarbazone s (nitrofurazones) and thiophene analogues were compared with their in vitr o and in vivo trypanocidal activity against Trypanosoma cruzi (Tulahuen str ain). 3D-QSAR models were obtained by applying the SIMCA methodology to the electrostatic and steric fields (CoMFA fields) of the molecules. Nitrofura zones bearing N-4 substituents. which cover a range of 14-17 Angstrom from the nitro group with a thickness of about 6 Angstrom when considering the e xtended conformer, produced complete survival in infected mice. The in vitr o model allows larger N-4 substituents than the SURVival model, but they mu st not bear positive centres in the region 15 16 Angstrom From the nitro gr oup. Moreover, the in vitro model is in agreement with the active site of t rypanothione reductase (TR). Both models can be of use in the design of nov el drugs bearing an amide-like group at a distance of 7-9 Angstrom from an easily reducible group. (C) 2001 Elsevier Science Ltd. All rights reserved.