Dongwei Kang

Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles

We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration.

Discovery and characterization of novel imidazopyridine derivative CHEQ-2 as a potent CDC25 inhibitor and promising anticancer drug candidate.

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation via the interactions with CDK/Cyclin complexes. Overexpression of CDC25 proteins is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, inhibiting CDC25 activity in cancer treatment appears a good therapeutic strategy. In this article, refinement of the initial hit XDW-1 by synthesis and screening of a focused compound library led to the identification of a novel set of imidazopyridine derivatives as potent CDC25 inhibitors. Among them, the most potent molecule was CHEQ-2, which could efficiently inhibit the activities of CDC25A/B enzymes as well as the proliferation of various different types of cancer cell lines in vitro assay. Moreover, CHEQ-2 triggered S-phase cell cycle arrest in MCF-7, HepG2 and HT-29 cell lines, accompanied by generation of ROS, mitochondrial dysfunction and apoptosis. Besides, oral administration of CHEQ-2 (10 mg/kg) significantly inhibited xenografted human liver tumor growth in nude mice, while demonstrated extremely low toxicity (LD50 > 2000 mg/kg). These findings make CHEQ-2 a good starting point for further investigation and structure modification.

Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants

This work follows on from our initial discovery of a series of piperidine-substituted thiophene[3,2-d]pyrimidine HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) ( J. Med. Chem. 2016 , 59 , 7991 - 8007 ). In the present study, we designed, synthesized, and biologically tested several series of new derivatives in order to investigate previously unexplored chemical space. Some of the synthesized compounds displayed single-digit nanomolar anti-HIV potencies against wild-type (WT) virus and a panel of NNRTI-resistant mutant viruses in MT-4 cells. Compound 25a was exceptionally potent against the whole viral panel, affording 3-4-fold enhancement of in vitro antiviral potency against WT, L100I, K103N, Y181C, Y188L, E138K, and K103N+Y181C and 10-fold enhancement against F227L+V106A relative to the reference drug etravirine (ETV) in the same cellular assay. The structure-activity relationships, pharmacokinetics, acute toxicity, and cardiotoxicity were also examined. Overall, the results indicate that 25a is a promising new drug candidate for treatment of HIV-1 infection.

Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities

CXCR4 plays vital roles in HIV-1 life cycle for its essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.

Novel diarylpyrimidines and diaryltriazines as potent HIV-1 NNRTIs with dramatically improved solubility: a patent evaluation of US20140378443A1

ABSTRACT Diarylpyrimidine and diaryltriazine derivatives, two representative structurally related classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with robust potencies against wild-type and several mutant strains of HIV-1, have attracted more and more attention in the last decade. However, they have been suffering from poor aqueous solubility. A series of novel diarylpyrimidines and diaryltriazines with solubilizing substituents attached to the central rings were reported as potent NNRTIs in the patent US20140378443A1. Some compounds exhibited potencies against wild-type HIV-1 which were comparable or even superior to those of dapivirine, etravirine and rilpivirine. In addition, dramatically enhanced solubilities were observed for these new compounds. Moreover, some structure optimization strategies for improving aqueous solubility are detailed in this review, providing new insights into development of next-generation NNRTIs endowed with favorable solubility. We anticipate that application of these strategies will ultimately lead to discovery of new anti-HIV drug candidates.

Synthesis and Biological Evaluation of a Series of 2-((1-substituted-1H-1,2,3-triazol-4-yl)methylthio)-6-(naphthalen-1-ylmethyl)pyrimidin-4(3H)-one As Potential HIV-1 Inhibitors

A series of novel S‐DABO derivatives with the substituted 1,2,3‐triazole moiety on the C‐2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide (B5b7), which exhibited similar HIV‐1 inhibitory potency (EC50 = 3.22 μm) compared with 3TC (EC50 = 2.24 μm). None of these compounds demonstrated inhibition against HIV‐2 replication. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed briefly.

First discovery of novel 3-hydroxy-quinazoline-2,4(1H,3H)-diones as specific anti-vaccinia and adenovirus agents via ‘privileged scaffold’ refining approach

Abstract A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7μM, which was 15 fold than that of the reference drug Cidofovir (EC50 =25μM). 24b13 was the most potent compound against adenovirus-2 with an EC50 value of 6.2μM, which proved lower than all the reference drugs. Preliminary structure–activity relationships were also discussed. To the best of our knowledge, no data are present in the literature on antiviral activity of 3-hydroxy-quinazoline-2,4(1H,3H)-diones against DNA-viruses. Thus, these findings warrant further investigations (library expansion and compound refinement) on this novel class of antiviral agents.

Synthesis and Preliminary Antiviral Activities of Piperidine‐substituted Purines against HIV and Influenza A/H1N1 Infections

We have developed a series of N2‐(1‐(substituted‐aryl)piperidin‐4‐yl)‐N6‐mesityl‐9H‐purine‐2,6‐diamine derivatives as potent antiviral agents. Preliminary biological evaluation indicated that nearly half of them possessed remarkable HIV inhibitory potencies in cellular assays. In particular, FZJ13 appeared to be the most notable one, which displayed anti‐HIV‐1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ05 displayed significant potency against influenza A/H1N1 (strain A/PR/8/34) in Madin–Darby canine kidney cells with EC50 values much lower than those of ribavirin, amantadine, and rimantadine. The results suggest that these novel purine derivatives have the potential to be further developed as new therapeutic agents against HIV‐1 or influenza virus.

Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach

In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structure–activity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication in the lower micromolar concentration range (EC50: 0.046–5.46 μM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.046 μM, CC50 of 99.9 μM and the viral selectivity index amounted to 2149. These values were much better than those of NVP (EC50 = 0.09 μM) and DDC (EC50 = 1.04 μM). Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC50 value of 4.06 μM, which was of the same order of magnitude as that of NVP (2.74 μM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.

Inhibitors of Influenza Virus Polymerase Acidic (PA) Endonuclease: Contemporary Developments and Perspectives

Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socioeconomic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need to develop additional small-molecular inhibitors that act on IFV proteins. One promising target is polymerase acidic (PA) endonuclease, which is a bridged dinuclear metalloenzyme that plays a crucial role in initiating IFV replication. During the past decade, intensive efforts have been made to develop small-molecular inhibitors of this endonuclease as candidate agents for treatment of IFV infection. Here, we review the current status of development of PA endonuclease inhibitors and we discuss the applicability of newer medicinal-chemistry strategies for the discovery more potent, selective, and safer inhibitors.