An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Abstract

Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanismof action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.

Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review

“…A set of dihydropyrimidinone (DHPM) derivatives, which probably act as NNRTIs and their activity against K103N/Y181C mutant RT are described [ 71 ]. A set of marine diterpenes (dolabelladienotriol, THD and its derivatives) has been docked with various mutant forms of RT containing mutations: K103N, V106M, Y188L; V106M, P225H; V106A, Y181I; V106A, Y181C, G190S; K103N, Y188L; K103N, Y188L, G190E [ 72 ].…”

“…It may be concluded that the existing application of the molecular docking to HIV-1 RT resistance studies lead mainly to the discovery of new molecules targeted at well-investigated mutant RT forms [ 67 , 68 , 69 , 70 , 71 , 72 ]. But some approaches are directed to research studies of known molecules targeted at comparatively rare RT mutants [ 65 , 66 , 73 ].…”

Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1H)-one

“…The interests of using DHPMs in medicinal chemistry is dramatically growing ( Figure 1 ) due to their therapeutic and pharmacological properties [ 4 , 5 ]. It has been reported that DHPMs can possess various biological activities including antiviral [ 6 , 7 ], antitumor [ 8 ], anti-inflammatory [ 9 ], antidiabetic [ 10 ], antibacterial [ 11 ], antifungal [ 12 ], anti-epileptic [ 13 ], antimalarial [ 14 ], and antileishmanial [ 15 ] and others upon suitable structural modification. The highly functionalized DHPM 10, termed MAL3-101, had been observed with effect of inducing breast cancer cell apoptosis [ 16 ].…”

Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines

“…Herein, we would like to disclose a novel interrupted Ugi reaction, exploiting for the first time the imidazole ring, as a soft nucleophile able to intramolecularly intercept the nascent nitrilium ion. This intermediate enables the formation of otherwise synthetically challenging substituted imidazopyrazines, in excellent yields and under mild reaction conditions (r.t. in MeOH) Multicomponent reactions represent a powerful chemical tool to expedite medicinal chemistry and early drug discovery programs [29], especially when combined with automation and flow synthesis [30,31,32].…”