Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Abstract

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

Keywords: HIV/AIDS; NNRTIs; bioisosteric replacement; cART; long-acting injectable; molecular hybridization; pharmaceutical strategies; prodrug; reverse transcriptase; scaffold hopping; structure- and fragment-based drug design.

Figure 1

Molecular hybridization strategy. Optimization of uracil-substituted DAPY, biphenyl-DAPY with a cyanomethyl linker, diarylbenzopyrimidines.

Figure 2

Bioisosterism strategy: Combination of bioisosterism with structure-based optimization of triazinylthioacetamide, piperidine-substituted thiophene[2,3-d]pyrimidine, and chiral hydroxyl-substituted biphenyl-diarylpyrimidine derivatives identified as potent HIV-1 NNRTIs.

Figure 3

Scaffold hopping strategy. Evolution of diverse DAPY-like derivatives.

Figure 4

Conformational restriction strategy. (A) Design of rigid heterocyclic scaffolds and intramolecular H-bonding as restricted factors for maintaining the “butterfly-like” conformation. (B) Design of conformationally restricted scaffolds by using chiral cyclopropane rings as restricted factors for maintaining the “butterfly-like” conformation in the binding pocket of RT. (C) Design of conformationally restricted derivatives by using stereochemical asymmetric geometry and extending dihedral angle as restricted factors for maintaining the “butterfly-like” conformation in the allosteric site of RT.

Figure 4

Conformational restriction strategy. (A) Design of rigid heterocyclic scaffolds and intramolecular H-bonding as restricted factors for maintaining the “butterfly-like” conformation. (B) Design of conformationally restricted scaffolds by using chiral cyclopropane rings as restricted factors for maintaining the “butterfly-like” conformation in the binding pocket of RT. (C) Design of conformationally restricted derivatives by using stereochemical asymmetric geometry and extending dihedral angle as restricted factors for maintaining the “butterfly-like” conformation in the allosteric site of RT.

Figure 5

Prodrug strategy. (A) Development of double-prodrugs by coupling D4T (NRTI) with Emivirine (NNRTI). (B) Design and synthesis of acetamide-substituted DOR and its prodrugs as potent HIV-1 NNRTIs.

Figure 6

Ligand efficiency strategy. Optimization of clinical candidate molecule Lersivirine on the basis of Capravirine scaffold refinement.

Figure 7

Structure-based optimization strategy. Design and development of novel aryl-ether scaffolds, pyridyl bearing fused bicyclic and indolylarylsulfones analogues by utilizing the crystal structures of RT.

Figure 8

Fragment hopping strategy. Flowchart of identification and optimization of thioacetamide dibenzopyrimidines as HIV-1 NNRTIs via the privileged fragment-based reconstruction approach.

Figure 9

High-throughput screening strategy. Schematic representation of the high-throughput screening approach for discovery of potent diverse scaffold HIV-1 RT inhibitors.

Figure 10

Compounds 66 (left) and 67 (middle) form a covalent bond inhibition with the thiol group of Cys181 in the HIV-1 Y181C RT (PDB codes: 5VQX and 5VQV). Covalent inhibition of compound 70 (right) to wild-type HIV-1 Reverse Transcriptase at Tyr181 residue using a fluorosulfate warhead (PDB 7KRD).

Figure 11

(A) Covalent Bonding Inhibition. Compounds 68 and 69 form covalent bonds with the Cys181. (B) The crystal structure for 71 (Left) and 72 (Right) is covalently bound to the hydroxyl oxygen atom of Tyr181 and side chain nitrogen atoms of Lys101 in the wild-type HIV-1 reverse transcriptase.

Figure 12

Targeting highly hydrophobic channels. Highly conserved regions of 73 and 74 which further developed into para-methylbenzoate analog 75 and the metamethylbenzoate analog 76 by CuAAC click reaction.

Figure 13

Targeting the hydrophilic solvent-exposed region. The potential binding solvent-exposed regions (red-colored region), which possibly accommodate structurally diverse moieties and form additional interactions, provide broad chemical space for substantial modifications.

Figure 14

Targeting dual sites. Various inhibitors targeting dual enzymes, RNase and IN.

Figure 15

FDA approved NNRTIs. The approved drugs for NNRTI from 1996 to 2018.