Thrilled by these promising results our quest for discoverin

Thrilled by these promising results, our quest for discovering new PPAR-γ/FFAR1 co-agonists was directed towards exploring the other two new scaffolds. So, in this proposed manuscript, we will describe our efforts regarding the synthesis, biological evaluation and molecular docking studies of the benzhydrol- and indole-based hybrids (series and -, respectively, ). Moreover, the effect on blood GSA 10 and plasma triglyceride levels were studied using the appropriate animal models. Despite the novelty of the previously introduced series , a branched biaryl chemotype with a stereogenic centre, it furnished mediocre potencies regarding the PPAR-γ receptor. It was expected that the Y-shaped structures of this series could help the compounds to fit into the two hydrophobic arms of PPAR-γ, while maintaining a suitable size that is not too bulky., , Nevertheless, promising FFAR1 receptor activity at low micromolar range persuaded us for further investigations. Thus, the benzhydrol-based series, , was introduced herein as a forked biphenyl chemotype. The phenyl shift in series was designed to allow the terminal oxygen to be widely open for optimized H-bonding interaction within the PPAR-γ binding pocket. This was based on predicted polar interaction between linker oxygen of the most active members of series and PPAR-γ central pocket residue (R288). As mentioned earlier, our explored scaffolds showed satisfactory results within previous investigations. In a similar fashion to series , the indole based-chemotype is another representative for the fused heterocycles having similarity with some reported glitazones showing comparable euglycemic and hypolipidemic activities to rosiglitazone., , However, this newly introduced series was designed with a two-carbon spacer, instead of the methoxy linker in series . Such linker extension was to bury the hydrophobic tail deeper into the binding site for better lodging. This might help to achieve significant anchoring of the TZD head and allow favored conformations that could minimize the steric clashes. Initial retrosynthetic dissection of the leads revealed that any of them can be broken down into three fragments; 5-benyl-thiazolidindione head, linker, and hydrophobic synthon. The key thiazolidinedione head group was prepared byan economic two-stage cyclization reaction (). Later, a parallel synthesis of both the hydrophobic-linker fragment and the 5-(4-hydroxybenylidene)-thiazolidindione head (), prior to their coupling, was attempted. Such a way would permit us to introduce diversity at the penultimate step (forward design). Unfortunately, the ionizable TZD head was found to interfere with the nucleophilic substitution or Mitsunobu coupling reactions needed for installing the hydrophobic-linker fragment. Moreover, the easily ionizable functionalities at (), the phenolic OH (pa ∼9.5) and amidic NH (pa ∼6.5), represent another challenge that could complicate the purification step of the products even if the problem of imide reactivity was tackled by protection. Thus, all designed compounds were prepared via a stepwise addition of fragments, starting from the hydrophobic trunk ‘left-hand-side’ and proceeding with building up the molecule, while keeping the TZD head as the last step (backward design)., It is worth noting that the linker was introduced along with hydrophobic trunk or with central aromatic moiety. The later tactic was more convenient regarding the yield and/or commercial availability of starting materials. Synthesis of series started with the acid-mediated condensation of the corresponding substituted benzhydrols () with 2-bromoethanol (). Subsequent S2 with 4-hydroxybenzaldehyde yielded the ether-aldehyde analogues (–). Finally, Knoevenagel condensation with followed by catalytic hydrogenation of the olefin moiety using NaBH/CoCl-dimethylglyoxime (Co-DMG) complex provided the target compounds (–) in good yields. The reduction of the benzylidenes was confirmed by the appearance of three double doublets in range of 3.00–5.50 ppm which appeared due to protons present on C-5 of TZD ring and methylene bridge.