Synthesis, mechanistic and synergy studies of diarylidenecyclohexanone derivatives as new antiplasmodial pharmacophores

AbstractDiarylidenecyclohexanone (DAC) derivatives (Ia-i,IIa-c andIIIa-b) were synthesized, characterized and screened for theirinvitro antiplasmodial activities against erythrocytic stages of chloroquine (CQ) sensitive and resistant strains ofP. falciparum by using SYBR green I fluorescence assay. SAR studies of DAC derivatives showed antiplasmodial activity in the order of 3-NO2 (Ib, IC50 0.95  µM) >  3-chloro (Id, IC50 3  µM) >  4-chloro (Ie, IC50 8.5  µM) >  2-chloro (Ic, IC50 13  µM). FurtherIb andId exhibited nearly equal potencies against CQ-resistant strainsP. falciparum Dd2, {IC50 1  µM (Ib) and 2.7  µM (Id)} andPfINDO {IC50 1.1  µM (Ib) and 2.5  µM (Id)}. Drug exposure followed by drug withdrawal-based stage-specific kill kinetic studies showed thatIb is shizonticidal within 3  h while the earliest killing actions against Trophozoites and Rings were seen at>3 h and>6  h, respectively. Combination studies of the most potent leads viz.Ib andId showed strong to moderate synergistic effects with Artemisinin ( ƩFIC50: 0.34 to 0.63) whereas no interaction ( ƩFIC50: 0.65 to 2.36) was observed with Chloroquine. The DACs showed significantinsilico binding affinity with β-haematin andP. falciparum lactate dehydrogenase (PfLDH) suggesting these to be the targets of their antiplasmodial action. High compliance with Lipinski rule of 5 and high selectivity index ofIb (105.3) andId (8.3) against HeLa cell line indicated tha...

Source: Medicinal Chemistry Research - October 1, 2018 Category: Chemistry Source Type: research