Synthesis of Novel Heterocyclic Ring‐Fused 18β‐Glycyrrhetinic Acid Derivatives with Antitumor and Antimetastatic Activity

Glycyrrhetinic acid (GA) is one of the most important triterpenoic acids shows many pharmacological effects, especially antitumor activity. GA triggers apoptosis in various tumor cell lines. However, the antitumor activity of GA is weak, thus the synthesis of new synthetic analogs with enhanced potency is needed. By introducing various five‐member fused heterocyclic rings at C‐2 and C‐3 positions, 18 novel GA derivatives were obtained. These compounds were evaluated for their inhibitory activity against the growth of eight different tumor cell lines using a SRB assay. The most active compound 37 showed IC₅₀ between 5.19 and 11.72 μm , which was about 11‐fold more potent than the lead compound GA. An apoptotic effect of GA and 37 was determined using flow cytometry and trypan blue exclusion assays. We also demonstrated here for the first time that GA and the synthetic derivatives exhibited inhibitory effect on migration of the tested tumor cells, especially 37 which was about 20‐fold more potent than GA on antimetastatic activity.     

Synthesis and Antimicrobial Activity of Some New Quinazolin-4(3H)-one Derivatives

A new series of 6-iodo-2-phenylquinazolin-4(3H)-one derivatives was prepared and screened for antimicrobial activity. The thioureide derivatives 4–6, the carbohydrazide derivatives 19–21 and 24 displayed excellent broad-spectrum antimicrobial activity. Some compounds showed moderate activity against Candida albicans and Pseudomonas aeruginosa. None of the tested compounds was as active as the reference standard drugs ampicillin and clotrimazole. The detailed synthesis, antimicrobial activity, and the minimum inhibitory concentrations (MIC) are reported.     

Cytostatic and Antiviral Activity Evaluations of Hydroxamic Derivatives of Some Non‐steroidal Anti‐inflammatory Drugs

Non‐steroidal anti‐inflammatory drugs (NSAID) pharmacophores are interesting in designing potential anticancer drugs. Indeed, numerous experimental, epidemiologic and clinical studies suggest that NSAIDs are promising anticancer drugs. Herein, NSAID hydroxamic acids 3a‐i were prepared by a new synthetic procedure and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts (WI38). Antiviral activity evaluation results indicated that 3f had only a minor activity against the influenza virus A/H1N1 subtype with a selectivity index of 7–10. On the other hand, the results of the in vitro cytostatic activity evaluations revealed that the majority of NSAID hydroxamic acid derivatives 3a – i exhibited a strong non‐specific antiproliferative effect at the highest concentration (100 μm ) on the tested cell line panel. Only compounds 3b , 3e and 3i exerted a differential dose‐dependent inhibitory activity against the growth of HeLa cells (p < 0.05) at concentration 10 μm . Among those three compounds, only compound 3b showed a selective cytostatic effect on HeLa in comparison with normal fibroblasts.     

Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure-activity relationships

Glycyrrhizic acid (18β-GL or GL) is a herbal drug with a broad spectrum of antiviral activities and pharmacological effects and multiple sites of action. Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). Here we tested the effects of 15 GL derivatives against EBV infection by scoring the numbers of cell expressing viral antigens and quantifying EBV DNA copy numbers in superinfected Raji cells. The derivatives were made either by transformation of GL on carboxyl and hydroxyl groups or by conjugation of amino acid residues into the carbohydrate part. We identified seven compounds active against EBV and all showed dose-dependent inhibition as determined by both assays. Among these active compounds, the introduction of amino acid residues into the GL carbohydrate part enhanced the antiviral activity in three of the seven active compounds. However, when Glu(OH)-OMe was substituted by Glu(OMe)-OMe, its antiviral activity was completely abolished. Introduction of potassium or ammonium salt to GL reduced the antiviral activity with no significant effect on cytotoxicity. The -isomer (18-GL) of 18β-GL was as potent as the β-form, but its sodium salt lost antiviral activity. The metabolic product of GL, 18β-glycyrrhetinic acid (18β-GA or GA), was 7.5-fold more active against EBV than its parental compound GL but, concomitantly, exhibited increased cytotoxicity resulting in a decreased therapeutic index.     

Effect of the derivatives of andrographolide on the morphology of <Emphasis Type="Italic">Bacillus subtilis</Emphasis>

Andrographis paniculata has been reported to have antiviral, antipyretic and anticancer activities. Andrographolide, an ent-labdane diterpene, is an active constituent in this plant. In this study, andrographolide (1) and its natural derivative 14-deoxy-11,12-didehydroandrographolide (2) and 5 other semisynthetic derivatives were tested for their activity against Grampositive and Gram-negative bacteria and Candida albicans. Only derivatives bearing a 14-acetyl group showed activity, and this activity was only against Gram-positive bacteria. 14-Acetylandrographolide showed the highest potency against Bacillus subtilis; the other 14-acetylandrographolides with additional substitution at the 3- and 19-hydroxyl groups showed lower activity against Gram-positive bacteria. The morphology of B. subtilis after being treated with 14-acetylandrographolide was investigated with TEM. This is the first report on 14-acetylandrographolide’s quantified antibacterial activity, and the crucial functional group of this ent-labdane that plays an important role in perturbing the morphogenesis of B. subtilis leading to cell death.     

抗菌抗病毒化合物的研究——鱼腥草素衍生物的合成

癸酰乙醛(n-壬基-β-酮醛)为清热解毒中草药鱼腥草的有效成分之一,其亚硫酸氢钠加成物(鱼腥草素)已在临床上用为抗菌消炎药物。这一事实导致我们合成了一些癸酰乙醛衍生物,目的为寻找更有效的抗病毒、抗菌药物。其中鱼腥草素异菸腙虽无抗病毒作用,但在体内、体外皆具有显著的抗结核活性,初步临床试验亦证明有一定的治疗效果。将甲壬酮与甲酸乙酯在金属钠存在下在无水苯中反应,形成的β-酮醛与相应的氨基化合物缩合,即获得所需要的最终产物。     

Synthesis and antiviral evaluation of 7-<Emphasis Type="Italic">O</Emphasis>-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV)

Aryl diketoacid (ADK) is well known for antiviral activity which can be enhanced by introduction of an aromatic arylmethyl substituent. A natural flavonoid quercetin has a 3,5-dihydroxychromone pharmacophore which is in bioisosteric relationship with the 1,3-diketoacid moiety of the ADK. Thus, it was of our interest to test the antiviral activity of the quercetin derivatives with an arylmethyl group attached. In this study, we prepared a series of the 7-O-arylmethylquercetin derivatives with various aromatic substituents and evaluated their antiviral activity against the SARS-associated coronavirus (SARS-CoV, SCV) as well as hepatitis C virus (HCV). Single difference in the aromatic substituent fine-tuned the biological activity of the 7-O-arylmethylquercetin derivatives to result in two different classes of derivatives selectively active against SCV and HCV.     

Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

Synthesis of New 2,3-Disubstituted 4 (3H)-Quinazolones and Related Products as Potential Antiviral Agents

Sixteen new 2,3-disubstituted 4 (3H)quinazolone derivatives were synthesized and evaluated for their antiviral activities against Gomphrena mosaic and Sunnhemp rosette virus. Most compounds show antiviral activity against Gomphrena mosaic virus.     

Acridine/acridone: a simple scaffold with a wide range of application in oncology

Background: The acridine scaffold is of interest since its DNA affinity and intercalative properties make it an important pharmacophore for the design of antitumor drugs targeting DNA. The global substitution on the heterocycle is crucial for a specific biological activity and also selectivity for tumor cells. Objective: Our aim is to review the most promising therapeutic developments within the vast research field dealing with acridine derivatives by pinpointing the new trends and the promising therapeutic directions. Methods: Our patent search covered the 2000 – 2008 period and was enriched with literature data. We focused on cancer/tumor-targeted new therapies where the acridine/acridone derivatives play a key role in the biological function studied. Results/conclusion: The most important therapies are those focusing specifically on tumor cells. Therefore, photodynamic therapy and hypoxia-selective drugs are of particular interest.     

Synthesis and Biological Evaluation of Strictosamide Derivatives with Improved Antiviral and Antiproliferative Activities

A series of novel derivatives of strictosamide were synthesized and biologically evaluated. Most of the new compounds exhibited improved activities than the parent compound strictosamide. Among them, compounds Ib and If possessed antiviral activities against influenza A virus (A/Jinan/15/90) with IC₅₀ values of 4.12 and 12.35 μg/mL, respectively. Compound Ie possessed antiviral activity against respiratory syncytial virus (RSV) with an IC₅₀ value of 9.58 μg/mL. Both compounds IIc and IId had moderate antiproliferative effects against five human cancer cell lines. The preliminary structure‐activity relationships were also concluded. This study provides a promising new template with potential antiviral activity.     

Synthesis and antiviral activity of fluorine-containing 4-arylaminoquinazolines

2-Methylthio-4-phenylamino-6,7,8-trifluoro-3H-quinazolin-4-one was synthesized by means of intramolecular cyclizations of S-methyl-N-(tetrafluorobenzoyl)isothiourea followed by a reaction with POCl₃ and nucleophilic substitution at the 4-position. The reactions of the synthesized compound with amines proceed, depending on their nature, via substitution of either the F(7) atom or the SMe fragment in the 2-position. The antiviral activity of the obtained 6,7,8-trifluoro-2-ethylthioquinazolin-4-ones was investigated using monkeypox virus, smallpox vaccine, and ectromelia virus. It is shown that fluorinated quinazoline derivatives have good prospects in the search for new active substances.     

Cidofovir: clinical experience and future perspectives on an acyclic nucleoside phosphonate analog of cytosine in the treatment of refractory and premalignant HPV-associated anal lesions

Background: Cidofovir, a nucleotide analog with antiviral activity against a broad range of DNA viruses including human papilloma viruses (HPV), is available off label to clinicians. Objective: To provide a better knowledge of pharmacology and effects when topically applied. Methods: After reviewing the chemistry, physiology, and animal studies, an overview of clinical studies is provided. Results/conclusions: Cidofovir, as a result of its antiviral and antiproliferative activity and its ability to induce apoptosis, can offer a solution for the treatment of severe recurrent HPV-induced lesions. It can also be used to attempt to treat dysplastic lesions and as an adjuvant treatment. The long-lasting antiviral activity allows infrequent dosing. As a rule, cidofovir applied on the skin is well tolerated, even in long-term treatment. The dose-limiting nephrotoxicity of the drug is not a concern in patients with a glomerular filtration rate within the normal range. Cidofovir has clearly influenced the landscape of refractory and dysplastic anogenital condylomata acuminata and its use has increased over the last decade. However, further controlled clinical trials are needed to assess the role of cidofovir and its derivatives.     

Synthesis and antiviral activity of quinoxalinedione 2,3(1H, 4H) derivatives

Syntheses and Antiviral Activities of Quinoxalinedione 2,3(1H,4H) Derivatives In our search for new virustatics, we have synthesized derivatives of quinoxaline-2,3(1H,4H)-dione and investigated their antiviral activities against various strains of herpes simplex virus types 1 and 2, vaccinia virus and vesicular stomatitis virus. None of the compounds showed antiviral activity comparable to that of 5-ethyl-2′-deoxyuridine (EtUdR).     

Study of the Effects on DNA of Two Novel Nucleoside Derivatives Synthesized as Potential Anti-HIV Agents

The pursuit of antiviral active compounds against different classes of viruses, in particular HIV, HBV, and HTLV is an area of important and intense research. In the current study, two novel nucleoside derivatives belonging to a new class of isoxazolidine were successfully synthesized as potential anti-HIV agents by replacement of the furanose ring by a N,O-heterocyclic ring Both compounds were investigated for biological activity, namely, mutagenic and antimutagenic properties. Using Salmonella typhimurium strains TA97, TA100, and TA102, both compounds proved to be nonmutagenic, which may be considered an encouraging result to further elucidate other biological activities. Antimutagenic testing of the synthesized compounds revealed that they are active against the base-pair substitution mutagen sodium azide. However, they did not show any indication as antimutagenic agents against hydrogen peroxide and mitomycin C (oxidative mutagens) or against nitrophenylenediamine (a base-pair substitution and frameshift mutagen). Structure–activity relationship is also discussed. Testing these compounds as antiviral agents is highly recommended.     

Pharmacokinetics and Antiepileptic Activity of Valproyl Hydroxamic Acid Derivatives

Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anti-convulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid—VPA-HA, N-(l-hydroxyethyl)-valpromide—HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(l-methoxyethyl) valpromide and N-( 1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.     

In vitro Antiviral Effects and 3D QSAR Study of Resveratrol Derivatives as Potent Inhibitors of Influenza H1N1 Neuraminidase

The anti-influenza virus activities of 50 resveratrol (RV: 3, 5, 4′-trihydroxy-trans-stilbene) derivatives were evaluated using a neuraminidase (NA) activity assay. The results showed that 35 compounds exerted an inhibitory effect on the NA activity of the influenza virus strain A/PR/8/34 (H1N1) with 50% inhibitory concentration (IC₅₀) values ranging from 3.56 to 186.1 μm . Next, the 35 RV derivatives were used to develop 3D quantitative structure–activity relationship (3D QSAR) models for understanding the chemical–biological interactions governing their activities against NA. The comparative molecular field analysis (CoMFA r² = 0.973, q² = 0.620, q_test² = 0.661) and the comparative molecular similarity indices analysis (CoMSIA r² = 0.956, q² = 0.610, q_test² = 0.531) were applied. Afterward, molecular docking was performed to study the molecular interactions between the RV derivatives and NA. Finally, a cytopathic effect (CPE) reduction assay was used to evaluate the antiviral effects of the RV derivatives in vitro. Time-of-addition studies demonstrated that the RV derivatives might have a direct effect on viral particle infectivity. Our results indicate that the RV derivatives are potentially useful antiviral compounds for new drug design and development for influenza treatment.     

中药协同抗真菌药物抗念珠菌的研究进展

侵袭性念珠菌感染已成为备受关注的公共卫生问题,而现行治疗念珠菌感染的药物有限,联合用药是一种实用有效的新药开发策略。从天然植物（尤其是药用植物）中提取的化合物及其衍生物与传统的抗真菌剂联合使用对杀灭念珠菌具有显著的协同作用。归纳了念珠菌对传统抗真菌药物的耐药情况,并总结了中药协同传统抗真菌药物的抑菌活性和抑菌机制,以期为抗念珠菌新型治疗策略的研究提供参考依据。     

Synthesis of anionic derivatives of myo-inositol and other polyols and investigation of their antiviral activity

The search for new, effective antiviral agents currently includes assessment of polyanionic compounds of various structures; these are highly active inhibitors of viral penetration into cells. The present report describes the preparation of phosphate and sulfate derivatives based on 2,3,4,5-tetra-O-benzyl-D,L-iditol, 1,12-dodecanediol, and a dimeric analog of inositol-containing phospholipids. The dimeric derivative, which contains two myo-inositol cyclitol rings linked by a single hydrophobic fragment, was synthesized at high yield using the H-phosphonate method. The antiviral activity of the series of compounds synthesized here was assessed against a panel of viruses. All were inactive against rhinoviruses; the disulfate of tetra-O-benzyl-D,L-iditol inhibited Coxsackie virus and had the greatest cytotoxicity; the disulfate of 1,2-dodecanediol was inactive against all viruses, while the diphosphate of 2,3,4,5-tetra-O-benzyl-D,L-iditol and the monosulfate of 1,2-dodecanediol were active against herpes simplex viruses types 1 and 2. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 1, pp. 6–12, January, 2008.