Optimization of Propafenone Analogues as Antimalarial Leads

Abstract

Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug’s potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogs was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multi-drug resistant K1 strain of P. falciparum compared to the 3D7 strain.

Exploiting the C-H bond in metal catalyzed C-C bond forming reactions

“…Then oxidative addition takes place towards XII and subsequent reductive elimination delivers the final product 56. 65 In the protocol reported above, aryl chlorides were inefficient. Still, it was tried to expand this reaction to aryl chlorides since they are again cheaper as the corresponding bromides and iodides and a vast number of them is readily available.…”

Design, synthesis and biological activity of phenylpropiofenone aminoalcoxy derivatives

“…Fenilpropiofenonska struktura je osnova velikog broja prirodnih i sintetskih farmakološki aktivnih jedinjenja različitog farmakodinamskog i farmakokinetičkog profila [1][2][3] . Među prirodnim proizvodima biljnog porekla, kao jedna od najznačajnijih podgrupa izdvajaju se α, β-nezasićeni ketoni, halkoni, derivati 1,3-diaril-2-propen-1-ona (Sl.1A).…”

“…Chiba i Ecker sa saradnicima su tokom višegodišnjih istraživanja izvršili sintezu i karakterizaciju, SAR i QSAR analizu oko 250 derivata propafenona sa strukturnim modifikacijama u aminskom i oksifenonskom delu molekula (Sl.1C). Sintetisani analozi su potencijalni antikancerski i antimalarijski lekovi 2 .…”

“…Tipična QSAR jednačina ima sledeći oblik: logY = a 0 +a 1 x 1 n1 +.....+a i x i ni +...+a n x n nn (2) gde eksponent može biti 1 ili 2 (linearna ili kvadratna zavisnost od datog parametra x).…”

“…Modulacija jonskih kanala predstavlja moderan pristup za eksperimentalna i klinička istraživanja u neprekidnom traganju za boljim lekovima 2,[52][53][54][55][56][57][58][59] . Modulatori jonskih kanala (pre svega modulatori kalijumskih kanala) poslednjih decenija postaju sve važniji ciljni molekuli u medicinskoj hemiji, jer jonski kanali kao sastavni delovi svake žive ćelije igraju ključnu ulogu u njenoj deobi, proliferaciji, ekscitaciji i apoptozi 60 .…”