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.     

Synthesis and In‐vitro Activity of 4′‐Modified Analogues of ddA as Potent Anti‐HIV Agents

This paper reports the synthesis of novel 4′‐hydrophobic pocket deoxythreosyl C‐nucleosides. The key threose‐like intermediates 9 and 14 were constructed from acyclic ketone derivatives, respectively. The antiviral activities of the synthesized compounds against the HIV‐1, HSV‐1, HSV‐2, and HCMV viruses were evaluated. The 9‐deaza‐adenine derivatives 10 and 20 showed good anti‐HIV activity without exhibiting significant cytotoxicity.     

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.     

7‐Chloro‐4‐quinolinyl Hydrazones: A Promising and Potent Class of Antileishmanial Compounds

In this work, we report the antileishmanial evaluation of twenty 7‐chloro‐4‐quinolinyl hydrazone derivatives ( 1 – 20 ). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC₅₀ in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds.     

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.     

Fungicide Activity of 5‐(4‐Chlorobenzylidene)‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐one against Cryptococcus Neoformans

The present work describes the synthesis and antifungal evaluation of new 5‐arylidene‐(Z)‐2‐dimethylamino‐1,3‐thiazol‐4‐ones 4a – f , obtained by the reaction of aromatic aldehydes 1 and rhodanine 2 followed by treatment with DMF. All compounds were tested against a panel of yeasts, hialohyphomycetes, and dermatophytes using the microbroth dilution method. Compounds 4a and 4c showed antifungal activity, with compound 4a being the most active one. Compound 4a demonstrated to be fungicidal rather than fungistatic and selective activity against Cryptococcus neoformans and dermatophytes. MIC₁₀₀, MIC₈₀, and MIC₅₀ of 4a were determined against a panel of clinical isolates of C. neoformans showing ranges of MICs between 2 and 16 μg/mL.     

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.     

Synthesis of 1‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐ difluoro‐5‐(2‐halo‐1‐hydroxyethyl)benzenes and related derivatives: “thymine replacement” analogs of deoxythymidine for evaluation as antiviral and anticancer agents

A group of unnatural 1‐(2‐deoxy‐β‐D ‐ribofuranosyl)‐2,4‐difluorobenzenes having a variety of C‐5 substituents, designed as thymidine mimics, were synthesized for evaluation as antiviral and anticancer agents. The regiospecific addition of HOBr (generated from N‐bromosuccinimide in aqueous dioxane) across the 5‐vinyl substituent ( 4 ) afforded the corresponding 5‐[‐CH(OH)CH₂Br] product ( 5 ), whereas reaction of 4 with iodine in the presence of iodic acid (HOI) yielded the 5‐[CH(OH)CH₂I] product ( 6 ). The related 5‐[‐CH(OH)CHX₂ (X = Br, I)] analogs ( 11 , 12 ) were similarly prepared from the (E)‐5‐(2‐halovinyl) precursors ( 9 , 10 ). Treatment of the 5‐[‐CH(OH)CH₂X (X = Br, I)] compounds ( 5 , 6 ) with NaOH in aqueous dioxane afforded the 5‐oxiranyl product ( 8 ). The 5‐[‐CH(OMe)CH₂I] compound ( 7 ) was prepared by reaction of the 5‐vinyl compound (4) with ICl in MeOH (MeOI). This group of compounds ( 5 – 8 , 11 , 12 ) showed similar (marginal) activity against varicella‐zoster virus thymidine kinase positive (VZV/TK⁺) and thymidine kinase deficient (VZV/TK^–) infected cells. Thus, the viral TK enzyme did not provide a gene therapeutic effect. This group of compounds, which were evaluated using a wide variety of antiviral assay systems [(herpes simplex virus HSV‐1, HSV‐2), varicella‐zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency virus (HIV‐1, HIV‐2)], showed that these unnatural C‐aryl nucleoside mimics are inactive antiviral agents. Their failure to exhibit antiviral/anticancer activity could be due to the fact that they are not phosphorylated to the 5′‐monophosphate, or that incorporation of the active 5′‐triphosphate into DNA does not produce a cytotoxic effect, and/or that these C‐aryl nucleoside mimics do not act as inhibitors of thymidylate synthase, which may be required to produce a cytotoxic effect. Drug Dev. Res. 52:492–499, 2001. © 2001 Wiley‐Liss, Inc.     

Indolizine Derivatives as HIV‐1 VIF–ElonginC Interaction Inhibitors

Compound 1 (VEC‐5) was identified as a potent small‐molecular HIV‐1 viron infectivity factor inhibitor that targets the viron infectivity factor–ElonginC interaction. A structure–activity relationship study was carried out to develop compounds with improved efficacy against HIV‐1 and 49 indolizine derivatives of three categories were designed and synthesized. We found that five compounds exhibited promising anti‐HIV‐1 activity, and the most active compound 2g had an IC₅₀ value of 11.0 μm . These results provide new information to develop highly potent small‐molecule HIV‐1 viron infectivity factor inhibitors.     

Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

This work presents synthesis and antimicrobial evaluation of nineteen 6‐alkylamino‐N–phenylpyrazine‐2‐carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution ( 3e , 4e ) with MIC = 5–10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug‐resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus (best MIC = 7.8 μm ), while Gram‐negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non‐toxic up to 100 μm .     

N‐hydroxy‐substituted 2‐aryl acetamide analogs: A novel class of HIV‐1 integrase inhibitors

An in silico method has been used to discover N‐hydroxy‐substituted 2‐aryl acetamide analogs as a new class of HIV‐1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b ) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV‐1 integrase inhibitors. Finally, six promising compounds (compounds 5b , 5c , 5e, 6–2c, 6–3b, and 6–5b ) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti‐HIV‐1 activity in a reporter gene‐based cell assay system, compounds 5d , 6s , and 6k were found as novel HIV‐1 integrase inhibitors due to its better selectivity index. Additionally, docking study revealed the importance of H‐bond as well as hydrophobic interactions with Asn155, Lys156, and Lys159 which were required for their anti‐HIV‐1 activity.     

Protective effects of 1,3‐diaryl‐2‐propen‐1‐one derivatives against H2O2‐induced damage in SK‐N‐MC cells

Alzheimer's disease (AD) is an age‐related neurodegenerative disorder of the central nervous system resulting in memory loss and dementia. Some of the associated pathogenic changes are amyloid peptide aggregation, excitotoxicity, oxidative stress and inflammation. Oxidative stress plays an indispensable role in the pathophysiology of AD. Therefore, antioxidant therapies appear to be promising approaches in dealing with AD patients. In that line, we evaluated the free radical scavenging capabilities of 13 different chalcones (1,3‐diphenyl‐2‐propen‐1‐one) derivatives against the free‐radical damaging effects of hydrogen peroxide (H₂O₂) on the SK‐N‐MC neuroblastoma cell line. Pretreatment of the cells for 3 h with 20 µ m of each of these derivatives (compounds 8 – 20 ) followed by exposure to 300 µ m H₂O₂ for 24 h indicated that all compounds, except compound 20 , were capable of restoring the viabilities of cells relative to the control (H₂O₂–treated) cells. The destructive effect of H₂O₂ on the adhesive behavior of the cells was almost totally restored by each of the derivatives. In addition, each of the derivatives except compounds 20 and 14 significantly reduced the extent of lipofuscin formation among the cells time‐dependently. Despite these activities, some of the derivatives, such as compounds 12 and 19 , did not reduce the H₂O₂‐induced intracellular ROS (reactive oxygen species) levels, meaning that these two derivatives act through a different mechanism other than free‐radical scavenging activity. On the other hand, for those derivatives acting as anti‐oxidants, structure–activity evaluation clearly revealed that the hydroxyl group of vanillin ring is required for their free‐radical scavenging activities. Copyright © 2010 John Wiley & Sons, Ltd.