Advances in drug structure-activity-relationships for the development of selenium-based compounds against HIV.

INTRODUCTION: Selenium possesses numerous advantageous properties in the field of medicine, and a variety of selenium-containing compounds have been documented to exhibit anti-HIV activity. This paper aims to categorize these compounds and conduct SAR analysis to offer guidance for drug design and optimization. AREAS COVERED: The authors present a comprehensive review of the reported SAR analysis conducted on selenium-based compounds against HIV, accompanied by a concise discussion regarding the pivotal role of selenium in drug development. EXPERT OPINION: In addition to the conventional bioisosterism strategy, advanced strategies such as covalent inhibition, fragment-based growth and drug repositioning can also be incorporated into research on selenium-containing anti-HIV drugs. Ebselen, which acts as an HIV capsid inhibitor, serves as a valuable probe compound for the discovery of novel HIV integrase inhibitors. Furthermore, it is crucial not to underestimate the potential toxicity associated with organic selenium compounds despite no reported instances of severe toxicity.

Punicalagin is a neuraminidase inhibitor of influenza viruses.

Influenza A virus (IAV) causes great morbidity and mortality worldwide every year. However, there are only a limited number of drugs clinically available against IAV infection. Further, emergence of drug-resistant strains can render those drugs ineffective. Thus there is an unmet medical need to develop new anti-influenza agents. In this study, we show that punicalagin from plants possesses strong anti-influenza activity with a low micromolar IC50 value in tissue culture. Using a battery of bioassays such as single-cycle replication assay, neuraminidase (NA) inhibition assay, and virus yield reduction assay, we demonstrate that the primary mechanism of action (MOA) of punicalagin is the NA-mediated viral release. Moreover, punicalagin can inhibit replication of different strains of influenza A and B viruses, including oseltamivir-resistant virus (NA/H274Y), indicating that punicalagin is a broad spectrum antiviral against both IAV and IBV. Further, although punicalagin targets NA like oseltamivir, it has a different MOA. These results suggest that punicalagin is an influenza NA inhibitor that may be further developed as a novel antiviral against influenza viruses.

Medicinal chemistry insights into novel CDC25 inhibitors.

Cell division cycle 25 (CDC25) phosphatases, a kind of cell cycle regulators, have become an attractive target for drug discovery, as they have been found to be over-expressed in various human cancer cells. Several CDC25 inhibitors have achieved significant attention in clinical trials with possible mechanistic actions. Prompted by the significance of CDC25 inhibitors with medicinal chemistry prospect, it is an apt time to review the various drug discovery methods involved in CDC25 drug discovery including high throughput screening (HTS), virtual screening (VS), fragment-based drug design, substitution decorating approach, structural simplification approach and scaffold hopping method to seek trends and identify promising new avenues of CDC25 drug discovery.

Identification of Potent Ebola Virus Entry Inhibitors with Suitable Properties for in Vivo Studies.

Previous studies identified an adamantane dipeptide piperazine 3.47 that inhibits Ebola virus (EBOV) infection by targeting the essential receptor Niemann-Pick C1 (NPC1). The physicochemical properties of 3.47 limit its potential for testing in vivo. Optimization by improving potency, reducing hydrophobicity, and replacing labile moieties identified 3.47 derivatives with improved in vitro ADME properties that are also highly active against EBOV infection, including when tested in the presence of 50% normal human serum (NHS). In addition, 3A4 was identified as the major cytochrome P450 isoform that metabolizes these compounds, and accordingly, mouse microsome stability was significantly improved when tested in the presence of the CYP3A4 inhibitor ritonavir that is approved for clinical use as a booster of anti-HIV drugs. Oral administration of the EBOV inhibitors with ritonavir resulted in a pharmacokinetic profile that supports a b.i.d. dosing regimen for efficacy studies in mice.

Recent progress in the structural modification and pharmacological activities of ligustrazine derivatives.

Ligustrazine is a main active fraction of the traditional medicine known as Ligusticum chuanxiong hort, which has been used as clinical medication for cerebral thrombosis, coronary heart disease and stenocardia recently. The rapid metabolism and short half-life of ligustrazine seriously limits its application in clinical practice. Therefore, derivatives of ligustrazine are designed and synthesized in our and other labs, including piperazine, cinnamic acid, styrene, acylguanidine, amides, curcumin and triterpenes derivatives of ligustrazine. Most of these compounds present better pharmacodynamics activities and more favorable pharmacokinetic properties compared to the parent compound. Besides, some new biological activities of these compounds are discovered. Hence, this review continues the previous review of our group as well as aims to highlight recent prominent advances in this field in the past ten years.

Design, synthesis, and biological evaluation of novel 5-Alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones as HIV-1 non-nucleoside reverse-transcriptase inhibitors.

A series of novel 5-alkyl-6-Adamantylmethylpyrimidin-4(3H)-ones bearing various substituents at the C-2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti-HIV activity in MT-4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild-type (WT) HIV-1 strain (IIIB ) with EC50 values in the range from 0.10 to 5.39 µm. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV-1 with EC50 values of 0.10 and 0.12 µm, respectively, which were more active than nevirapine (NVP) in the same assay. In addition, HIV-1 reverse-transcriptase (RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV-1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure-activity relationship (SAR) and the molecular modeling analysis of these new derivatives are also discussed.

Pharmacokinetics and metabolism of Chf197, a ligustrazine derivative, in rats.

Ligustrazine is the most abundant and bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular diseases. Chf197 is one of the structurally modified ligustrazine derivatives in a purpose of overcoming the rapid metabolism and short half-life of original. The plasma and urine pharmacokinetics of Chf197 in rats were studied after intravenous or intraperitoneal injection of Chf197 with the validated RP-HPLC method. The pharmacokinetic parameters of Chf197 injected intravenously 20 mg/kg were as follows: Cmax , 1.44 ± 0.4 mg/L; Tmax , 0.08 h; t1/2 , 3.03 ± 1.67 h; AUC, 3.85 ± 3.88 h/L; Vd , 31.66 ± 11.79L/kg; and CL, 9.29 ± 4.92 l/h/kg. Dose-dependent pharmacokinetics was observed, and a significantly higher dose-normalized AUC after intravenous administration was obtained than that after intraperitoneal administration. A possible metabolite was detected at about 3.1 min, and full-scan mass spectrum was adopted to predict its possible structure.

Strategies for the Discovery of Target-Specific or Isoform-Selective Modulators.

Currently, the creation of class- and isoform-selective modulators of biologically important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, especially at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, we discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and we illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active molecules (hit-to-lead and lead-to-candidate efforts). We also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.

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.

DLJ14, a novel chemo-sensitization agent, enhances therapeutic effects of adriamycin against MCF-7/A cells both in vitro and in vivo.

OBJECTIVES: We investigated the chemo-sensitization of a ligustrazine derivate, (E)-2-(2, 4-dimethoxystyryl)-3, 5, 6-trimethylpyrazine (DLJ14) on Adriamycin (Adr, Wanle, Shenzhen, China)-resistant human breast cancer (MCF-7/A) cells both in vivo and in vitro. METHODS: The antitumour effects of DLJ14 and Adr was observed in MCF-7/A cells by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro and was evaluated by MCF-7/A xenografts in nude mice. The intracellular Adr accumulation was assessed by mean fluorescence intensity of Adr. The messenger RNA level of glutathione (GSH) S-transferase (GST)π in MCF-7/A cells was determined by real-time reverse transcription PCR assay. The expression of GSTπ, c-jun NH2 -terminal kinase (JNK) and phosphor-JNK (p-JNK) was detected by Western blotting method. KEY FINDINGS: The MTT results showed that DLJ14 exhibited a weak inhibition on proliferation of both MCF-7 and MCF-7/A cells, in contrast with the strong inhibition of verapamil. When DLJ14 is combined with Adr, the inhibitory effect on MCF-7/A cells and MCF-7/A xenografts was enhanced significantly through increasing intracellular accumulation of Adr by inhibition of GSH level and the activity of GSH peroxidase and GST. Moreover, DLJ14 could downregulate the expression of GSTπ and increase the expression of JNK and p-JNK in MCF-7/A cells or in xenografts. CONCLUSION: DLJ14 is a promising chemo-sensitization candidate for the reversal of multidrug resistance in cancers.

Design, synthesis, and biological evaluation of novel 3,5-disubstituted-1,2,6-thiadiazine-1,1-dione derivatives as HIV-1 NNRTIs.

On the basis of structural features, binding mode, and structure-activity relationship studies of two pyrimidine-derived non-nucleoside reverse-transcriptase inhibitors, DABOs, and diaryl pyrimidines, a novel class of 1,2,6-thiadiazine-1,1-dione derivatives were rationally designed using the strategies of bioisosterism and molecular hybridization, synthesized, and evaluated for their anti-HIV activity in MT4 cell cultures. Three compounds were found to have moderate activity against HIV-1 replication with EC50 values ranging from 23 to 32 µm. To further confirm the binding target, compound IIg was selected to conduct an HIV-1 reverse-transcriptase inhibitory assay. In addition, preliminary structure-activity relationship analysis among the newly synthesized compounds was discussed, and the binding mode of the active compound IIg was rationalized by molecular docking and physicochemical studies.

Mechanism of tetramethylpyrazine analogue CXC195 inhibition of hydrogen peroxide-induced apoptosis in human endothelial cells.

A tetramethylpyrazine analogue, CXC195, was synthesized by the Boekelheide reaction, in which the second methyl group of tetramethylpyrazine (TMP) was replaced with (4,4'-fluorine) diphenyl-methyl-1-piperazidine, the active group of flunarizine. We have observed protective effects of CXC195 on vascular endothelial cell survival under oxidative stress in previous study. The aim of the present study was to investigate the effects of CXC195 against apoptosis induced by hydrogen peroxide in human umbilical vein endothelial cells (HUVECs). Accordingly, a biochemical approach to elucidate the apoptotic signal pathways was attempted. HUVECs were exposed to 150 muM H(2)O(2) for 12 h, resulting in an increase of apoptotic cells assessed by the nuclear staining assay and flow cytometry. Mitochondrial membrane potential was detected by retention of rhodamine123. The concentration of free intracellular calcium was determined by fura-2/AM fluorometry. Co-incubation with CXC195 reduced the percentage of apoptotic cells and inhibited the loss of mitochondrial membrane potential and intracellular calcium overload induced by H(2)O(2). Induction of p53, the activation of caspase-3 by H(2)O(2) which accompanying downregulation of bcl-2, was blocked by CXC195. In addition, CXC195 clearly improved phosphorylation levels of the antiapoptotic extracellular signal-regulated kinase-1/2 (ERK1/2) in cells undergoing oxidative damage. Moreover, CXC195 showed stronger effects on inhibition of apoptotic cells and loss of mitochondrial membrane potential and activation of phosphorylated ERK1/2 than TMP. These results suggest that CXC195 prevents reactive oxygen species-induced apoptosis through inhibition of the mitochondria-dependent caspase-3 pathway and ERK pathway to show a better beneficial effect in protecting endothelial cells than TMP.

Synthesis and biological evaluation of novel 2-(substituted phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs.

A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC(50) ranging from 4.48microM to 0.18microM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-5-methylpyrimidin-4(3H)-one 4b3 was identified as the most promising compound (EC(50) = 0.18+/-0.06microM, CC(50) >243.56microM, SI >1326). The structure-activity relationship (SAR) of these new congeners is discussed.

1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

A novel series of 1,2,3-thiadiazole thioacetanilide (TTA) derivatives have been designed, synthesized and evaluated for its anti-HIV activities in MT-4 cells. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Among them, 2-[4-(2,4-dichlorophenyl)-1,2,3-thiadiazol-5-ylthio]-N-(2-nitrophenyl)acetamide 7d2 was identified as the most promising compound (EC(50)=0.059+/-0.02 microM, CC(50)>283.25 microM, SI>4883). The structure-activity relationship (SAR) of these novel structural congeners is discussed.

Parthenogenetic activation of mouse oocytes by strontium chloride: a search for the best conditions.

Strontium has been successfully used to induce activation of mouse oocytes in nuclear transfer and other experiments, but the optimum treatment conditions have not been studied systematically. When cumulus-free oocytes were treated with 10mM SrCl(2) for 0.5-5h, activation rates (88.4+/-4.1 to 91.2+/-2.7%) did not differ (mean+/-S.E.; P>0.2), but rate of blastulation (57.3+/-3.5%) and cell number per blastocyst (45.0+/-2.4) were the highest after treatment for 2.5h. When treated with 1-20mM SrCl(2) for 2.5h, the activation rate and cell number per blastocyst were higher (P<0.02) after 10mM SrCl(2) treatment than other treatments. The best activation and development were obtained with Ca(2+)-free Sr(2+) medium, but the activation rate was low (37.7+/-1.6%) in Ca(2+)-containing medium. Activation rates were the same, regardless of the presence or absence of cytochalasin B (CB) in the activating medium, but the blastulation rate was higher (P<0.001) in the presence of CB. Only 70% of the cumulus-enclosed oocytes were activated and 10% blastulated after a 10 min exposure to 1.6mM SrCl(2), and many lysed, with increased intensity of Sr(2+) treatment. The presence of CB in SrCl(2) medium markedly reduced lysis of cumulus-enclosed oocytes. Media M16 and CZB did not differ when used as activating media. Only 10.5% of the oocytes collected 13 h post hCG were activated by Sr(2+) treatment alone, with 34% blastulating, but rates of activation and blastulation increased (P<0.001) to 94 and 60%, respectively, when they were further treated with 6-dimethylaminopurine (6-DMAP). The total and ICM cell numbers were less (P<0.001) in parthenotes than in the in vivo fertilized embryos. In conclusion, the concentration and duration of SrCl(2) treatment and the presence or absence of CB in activating medium and cumulus cells had marked effects on mouse oocyte activation and development. To obtain the best activation and development, cumulus-free oocytes collected 18 h post hCG should be treated for 2.5h with 10mM SrCl(2) in Ca(2+)-free medium supplemented with 5 microg/mL of CB.