Antileishmanial pyrazolopyridine derivatives: synthesis and structure-activity relationship analysis.
Three series of 4-anilino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic esters were synthesized as part of a program to study potential anti-Leishmania drugs. These compounds were obtained by a condensation reaction of 4-chloro-1H-pyrazolo[3,4-b]pyridine with several aniline derivatives. Some of them were also obtained by an alternative pathway involving a Mannich-type reaction. The hydrophobic parameter, log P, was determined by shake-flask methodology, and using the Hansch-Fujita addictive hydrophobic fragmental constants. These compounds were tested against promastigote forms of Leishmania amazonensis. The very promising results showed the 3'-diethylaminomethyl-substituted compounds as the most active [IC50 = 0.39 (21) and 0.12 microM (22)]. Molecular modeling, using semiempirical AM1 method, predicted the most active compounds through the low-energy conformers superimposition on amodiaquine structure. QSAR equations, derived from the IC50 values against L. amazonensis, showed the hydrophobic (log P) and Sterimol steric (L and B2) parameters as most significant contributions on biological activity.
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, 23851-970, Seropédica/RJ--Brazil.
Heloisa
H
de Mello
Aurea
A
Echevarria
Alice M
AM
Bernardino
Marilene
M
Canto-Cavalheiro
Leonor L
LL
Leon
D000818:Animals; D007891:Leishmania / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D011720:Pyrazoles; D011725:Pyridines; D014344:Trypanocidal Agents