Synthesis and Docking Analysis of New Heterocyclic System N1, N4-bis ((2-chloroquinolin-3-yl) methylene) benzene-1, 4-diamine as Potential Human AKT1 Inhibitor

In recent years, the chemistry of 2-chloroquinoline-3-carbaldehydes have received considerable attention owing to their synthetic and effective biological importance which exhibits a wide variety of biological activity, N1,N4-bis((2-chloroquinolin-3-yl)methylene)benzene-1,4-diamine derivatives that synthesized from 2-chloroquinoline-3-carbaldehydes may have biological effects. As the inhibitor of AKT1 (RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1), the aforementioned compounds may have implication in preventing complications of cancers.
A group of N1, N4-bis ((2-chloroquinolin-3-yl) methylene) benzene-1, 4-diamine derivatives (3a-3i) (H, 6-Me, 6-OMe, 6-OEt, 6-Cl, 7-Me, 6-Et, 6-Isopropyl, 7-Cl) were synthesized, and theoretically evaluated for their inhibitory as Potential Human AKT1 Inhibitors via docking process. The docking calculation was done in GOLD 5.2.2 software using Genetic algorithm.
Compounds 3b (6-Me) and 3d (6-OEt) showed the best inhibitory potency by GOLD score value of 113.76 and 107.58 respectively.
Some of the best models formed strong hydrogen bonds with Asn 49, Lys 220, Ser 157, Arg 225 and Trp 76 via quinoline moiety and nitrogen of quinolone ring (Figure 1). pi-pi interaction between Lys 220, Trp 76, Tyr 224, Arg 225, Ile 80, and Asn 49 quinoline moiety was one of the common factor in enzyme-inhibitor junction.
It was found that both hydrogen bonding and hydrophobic interactions are important in function of biological molecules, especially for inhibition in a complex.
Keywords: AKT1 Inhibitors, cancer, Docking Analysis, Heterocyclic compound, Quinoline derivatives.