Design,Synthesis, and Biological Evaluation of Novel 4‐Aminopiperidinyl‐linked 3,5‐Disubstituted‐1,2,6‐thiadiazine‐1,1‐dione Derivatives as HIV‐1 NNRTIs

Based on the hybridization of the privileged fragments in DABO and DAPY‐typed HIV‐1 NNRTIs, a novel series of 4‐aminopiperidinyl‐linked 3,5‐disubstituted‐1,2,6‐thiadiazine‐1,1‐dione derivatives were designed, synthesized, and evaluated for their in vitro anti‐HIV activities in MT‐4 cells. Most of the target compounds showed weak inhibitory activity against WT HIV‐1. In order to confirm the mode of action of the target compounds, representative compounds Ba8 and Bb8 were selected to perform the HIV‐1 RT inhibitory assay. In this assay, Ba8 and Bb8 displayed good activity with IC₅₀ values of 3.15 and 1.52 μm , respectively. Additionally, preliminary structure–activity relationships (SARs) analysis and molecular docking studies of newly synthesized compounds are also discussed.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Molecular Modeling,Synthesis, and Anti‐HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐HIV activity and the molecules having sulfonamide linkages were the most potent HIV‐RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti‐HIV drugs. In vitro screening was performed using HIV‐1 strain IIIB in MT‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV‐1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations.     

Design,Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

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Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

Novel series of 3‐O‐arylalkylbenzamide and 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives were synthesized and evaluated for their on‐target activity and antibacterial activity. The results indicated that the 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives possessed much better on‐target activity and antibacterial activity than the 3‐O‐arylalkylbenzamide derivatives. Among them, 3‐O‐chlorobenzyl derivative 36 was the most effective in antibacterial activity (0.5, 4, and 8 μg/mL) against Bacillus subtilis ATCC9372, methicillin‐resistant Staphylococcus aureus ATCC29213, and penicillin‐resistant Staphylococcus aureus PR, while 3‐O‐methylbenzyl derivative 41 only exhibited the most potent activity (2 μg/mL) against Staphylococcus aureus ATCC25923.     

Design,Synthesis and Biological Evaluation of 3,9‐diazatetraasteranes as Novel Matrilysin Inhibitors

Matrilysin is an ideal biological target to develop novel inhibitors because it is overexpressed in malignant tumour cells. A series of 3,9‐diazatetraasteranes was designed as inhibitors of matrilysin, which was an ideal biological target because it is responsible for aggressive malignant phenotypes and poor prognoses implicated in many cancers. Docking simulation supported the initial pharmacophore hypothesis and suggested a common interaction mechanism of 3,9‐diazatetraasteranes with the catalytic site of matrilysin. The 3,9‐diazatetraasteranes were synthesized by the photocyclization of 4‐aryl‐1,4‐dihydropyridines, and their structures were determined using ¹H NMR, ¹³C NMR and MS. The inhibitory activities of these compounds on matrilysin were investigated in vitro using an MTT assay in A549 (small cell lung cancer) cells. The results show that the 3,9‐diazatetraasteranes can inhibit the growth of A549 tumour cells. The best IC₅₀ value is approximately 50 μm . This result indicates that 3,9‐diazatetraasteranes will be useful pharmacological tools for the investigation of matrilysin inhibitors.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.