Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

Identification of 1‐phenyl‐4‐cyano‐5‐aminopyrazoles as novel ecdysone receptor ligands by virtual screening,structural optimization,and biological evaluations

Ecdysteroids initiate the molting process in insects by binding to the ecdysone receptor (EcR), which is a promising target for identifying insect growth regulators. This paper presents an in silico/in vitro screening procedure for identifying new EcR ligands. The three‐step virtual screening procedure uses a three‐dimensional pharmacophore model, docking and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) rescoring routine. A novel hit ( VS14 ) with good binding activity against Plutella xylostella EcR was identified from a library of over 200,000 chemicals. Subsequently, the 1‐phenyl‐4‐cyano‐5‐aminopyrazole scaffold and twelve EcR ligands were synthesized. Their IC₅₀ values against Plutella xylostella EcR ranged from 0.64 to 23.21 μm . Furthermore, a preliminary analysis of the structure–activity relationship for novel scaffolds provided a basis for designing new ligands with improved activity.     

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.     

Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking

Lysine‐specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore‐based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC₅₀ values in a range of 2.41–101 μm . Furthermore, compound XZ 09 exhibited less inhibition against the homologous monoamine oxidase A (MAO‐A) and B (MAO‐B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers.     

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, FZJ 13 appeared to be the most notable one, which displayed anti‐HIV‐1 activity compared to 3TC. Moreover, an unexpected finding was that FZJ 05 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 HIV‐1 Integrase Inhibitors: Pharmacophore Mapping,Virtual Screening,Molecular Docking,Synthesis, and Biological Evaluation

HIV‐1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV‐1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q_fit value were used to design 30 molecules bearing pteridine ring and were docked on co‐crystal structure of HIV‐1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave‐assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti‐HIV activity against the replication of HIV‐1 (IIIB) in MT‐4 cells. The used approach of molecular docking and anti‐HIV activity data of designed molecules will provide significant insights to discover novel HIV‐1 Integrase Inhibitors.