Pyridyl derivatives of benzaldehyde as potential antisickling agents.
Compounds that bind to sickle hemoglobin (Hb S) producing an allosteric shift to the high-affinity Hb S that does not polymerize are being developed to treat sickle cell anemia (SCA). In this study, three series of pyridyl derivatives of substituted benzaldehydes (Classes I-III) that combine structural features of two previously determined potent antisickling agents, vanillin and pyridoxal, were synthesized. When analyzed with normal human whole blood, the compounds form Schiff-base adducts with Hb and left shift the oxygen equilibrium curve (OEC) to the more soluble high-affinity Hb, more than vanillin or pyridoxal. Generally, Class-I compounds with an aromatic aldehyde located ortho to the pyridyl substituent are the most potent, followed by the Class-II compounds with the aldehyde at the meta-position. Class-III compounds with the aldehyde at the para position show the weakest activity. The structure-activity studies of these pyridyl derivatives of substituted benzaldehydes demonstrate significant allosteric potency that may be useful for treating SCA.
Nnamani
Ijeoma N
IN
School of Medicine, University of Virginia, Charlottesville, VA 22901, USA.
Joshi
Gajanan S
GS
Danso-Danquah
Richmond
R
Abdulmalik
Osheiza
O
Asakura
Toshio
T
Abraham
Donald J
DJ
Safo
Martin K
MK
D000986:Antisickling Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D001547:Benzaldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010100:Oxygen / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000986:Antisickling Agents; D001547:Benzaldehydes; D011725:Pyridines; C023666:pyridine; D010100:Oxygen; C032175:benzaldehyde