Novel Tsao Derivatives. Synthesis and Anti-HIV-1 Activity of Allofuranosyl-TSAO-T Analogues

Abstract

Novel TSAO-T analogues, in which the ribofuranosyl moiety has been replaced by an hexofuranosyl sugar moiety, have been prepared and evaluated for their inhibitory effect on HIV-1 replication in cell culture. In contrast to the prototype compound TSAO-T, the hexofuranosyl derivatives proved not active at subtoxic concentrations.

     

Synthesis and Anti-HIV-1 Activity of 4- and 5-Substituted 1,2,3-Triazole-TSAO Derivatives

Abstract

Several 4- or 5-monosubstituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO-T) have been prepared and evaluated for their inhibitory effect against HIV-1-induced cytopathicity.     

The Synthesis of (1,3,4-Oxadiazol-2-yl)Acrylic Acid Derivatives with Antibacterial and Protistocidal Activities

A series of new 1,3,4-oxadiazol-2-yl-acrylic acids was synthesized by cyclization of 4-(2-R-hydrazino)- 4-oxo-2-butenic acids, and their antibacterial and protistocidal activities were studied. The p-substituted benzyl derivatives in the Z-form were shown to exhibit a high protistocidal activity, which exceeded that of the reference drug Baycox (toltrazuril) by several times, whereas the 3-hydroxy-2-naphthyl derivative, in addition to a very high protistocidal activity, also exhibited a moderate antibacterial activity.     

Synthesis and Biological Activities of Phosphonylalkylpurine Derivatives

Abstract

Syntheses and biological activities of 2-phosphonylmethoxy-ethyl (PME) purine analogs are described.     

Synthesis of Coumarin Derivatives with Cytotoxic,Antibacterial and Antifungal Activity

The synthesis and selective biological screening of 7-hydroxy-4-methyl-2H-chromen-2-one (2), 7-hydroxy-4,5-dimethyl-2H-chromen-2-one (15) and some of their derivatives were carried out. Compound 13 was found to be most potent cytotoxic agent with LD₅₀ = 126.69 μg/ml. In antibacterial assay the compounds showed a broad spectrum of activities. Compound 11 exhibited a very high degree of plant growth inhibition at three levels of concentration. Compound 4 showed very promising antifungal activity against Candida albicans. Compounds 12 and 13 demonstrated excellent antioxidant activity.     

Anti-HIV-1 Activities of 1,3-Dioxolane Guanine and 2,6-Diaminopurine Dioxolane

Abstract

DXG and its prodrug DAPD have been demonstrated to be effective inhibitors of HIV-1 in various cells. The EC₅₀s for DXG were 0.032 μM in CBMCs and 0.05 μM in MT-4 cells, which were generally equipotent as 3TC. 3TC-resistant, but not AZT-resistant, HIV-1 had minimum diminished sensitivity to the compounds. Both DXG and DAPD were non-toxic to cells up to 500 μM.     

Synthesis of Selenium-Containing Chitosan Derivatives and Their Antibacterial Activity

Applied Biochemistry and Microbiology - The interaction of chitosan with 3-(chloromethyl)-[1,2,4]selendiazole[4,5-a]pyridin-4 bromide results in water-soluble, selenium-containing, cationic...     

Synthesis and Antitumor Activities of 5-Fluorouracil Derivatives

Abstract

1-Carbonyl 5-fluorouracil derivatives,5′-acyl-5-fluorouridines, and 5-fluorouridilic acid esters were synthesized and their antitumor activities were tested.     

Antibacterial and Inducer Activities for Tetracycline Resistance by Its Derivatives and Analogues

Antibacterial and inducer activities of thirteen TC derivatives were investigated for tetracycline (TC) resistance in staphylococcus aureus. Four compounds of the TC derivatives were not able to induce the resistance to TC in Staphylococcus aureus MS3937 r_ms7 (TC)⁺ harboring an inducible TC resistance determinant located on a plasmid. The 12a-hydroxy position seems to be essential for the inducer activity.     

Synthesis of New N-Benzoyl-N'-Triazine Thiourea Derivatives and Their Antibacterial Activity

Russian Journal of Bioorganic Chemistry - A series of new N-benzoyl-N'-triazine thiourea derivatives have been synthesized via the reaction of...     

Synthesis,Molecular Docking,and In Vitro Antibacterial Activities of Some Novel Aminobenzylnaphthol Derivatives via One-Pot Three-Component Reaction

Russian Journal of Bioorganic Chemistry - This work provides the first example of incorporating the thiazole moiety into the aminobenzylnaphthol i.e. Betti base. A series of novel synthesized Betti...     

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-Oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with β-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle.The human immunodeficiency virus (HIV)⁷ pandemic is a medical challenge and represents the public health crisis of our time (1–5). Antiretroviral treatment achieves long-lasting viral suppression and, subsequently, reduces the morbidity and mortality of HIV-infected individuals. However, current drugs do not eradicate HIV infection and lifelong treatment might be needed (2).Emerging drug-resistant HIV viruses, in patients receiving high active antiretroviral treatment, urgently needs the development of new antiretroviral molecules designed to inhibit resistant viruses, because many patients treated during the past decades harbor viral strains with reduced susceptibilities to many if not all available drugs (2, 6). In this matter, pentacyclic triterpenes represent a varied class of natural products presenting antitumor and antiviral activities (7–9). A well studied pentacyclic lupane-type triterpene is the betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid), widely distributed throughout the plant kingdom, which presents anti-inflammatory, anti-malarial, and anti-HIV-1 effects in vitro (7, 9, 10). Although its mechanism of action has not been fully determined, it has been reported that some lupane-type triterpene derivatives impair HIV-1 fusion through interacting with the viral glycoprotein gp41, or disrupting the assembly and budding of emerging viral particles in infected target cells (reviewed in Ref. 9).In the present work, we aimed to test the ability of several non-acid lupane-type triterpene, natural or derivative compounds, to inhibit HIV-1 viral infection and to determine the mechanism of action. Our results indicate that the semi-synthetic 30-oxo-calenduladiol, compound 1, specifically interacts with the G protein-coupled CCR5 chemokine receptor, acting as an antagonist, inhibiting R5-tropic HIV-1 viral infection and CCL5 (regulated on activation normal T expressed and secreted (RANTES) chemokine)-mediated CCR5 internalization, cell signaling, and chemotaxis.     

Synthesis,Cytotoxic, and Antibacterial Evaluation of Quinazolinone Derivatives with Substituted Amino Moiety

A series of novel quinazolinone derivatives containing a substituted amino moiety were synthesized, evaluated for their cytotoxic and antibacterial activities. The results of MTT assay showed that all synthesized target compounds 5A  –  5O showed potent cytotoxicity against SGC‐7901 (IC₅₀, 0.72 – 1.41 μm ). Moreover, the compounds 5D , 5I , and 5K showed better selectivity as compared with positive controls pemetrexed and MTX due to weak cytotoxicity against normal tissue cell line HUVSMC. Among synthesized compounds, the compounds 5E , 5J , 5L , and 5N showed broad‐spectrum cytotoxic activities against at least four cancer cell lines at a micromolar level. The results of antibacteria evaluation revealed that all synthesized compounds showed good to moderate antibacterial activities against Gram‐negative bacteria Escherichia coli. Among them, the MIC values of the compounds 5C , 5F , and 5M were 0.31 μg/mL.     

5-Alkylthiomethyl Derivatives of 2'-Deoxyuridine: Synthesis and Antibacterial Activity

Russian Journal of Bioorganic Chemistry - To obtain nucleoside derivatives with antibacterial activity, we have proposed three ways of the synthesis of 5-alkylthiomethyl-2'-deoxyuridines, which...     

Synthesis and Herbicidal Activities of 1,2-Benzisoxazole-3-acetamide Derivatives

Many 1,2-benzisoxazole-3-acetamides were synthesized and their herbicidal activities in the paddy field were studied. Of the compounds tested, N-α,α-dimethylbenzyl-2-bromo-(1,2-benzisoxazol-3-yl)acetamide 10a was the most effective. Details of the synthesis and the results of herbicidal evaluations are given.     

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6-Methylpyridine Moiety

A series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles ( 15a – t and 16a – f ) were synthesized and their antibacterial activities were evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1–2 μg/mL) and 16d (MIC=0.5 μg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.     

Synthesis and Docking Studies of Novel Carbazole-Thiazolidinedione Hybrid Derivatives as Antibacterial Agents

Russian Journal of Bioorganic Chemistry - A series of novel carbazol-thiazolidinedione hybrid derivatives were designed, synthesised and screened for antimicrobial activity against gram-positive...     

Synthesis and Biological Activities of New 1,2,4-Triazol-3-one Derivatives

New 2-phenacyl-1,2,4-triazol-3-ones were obtained by the reaction of 5-alkyl-1,2,4-triazol-3-ones with α-bromoacetophenone in an alkaline medium. Selective reduction of the side chain carbonyl group to hydroxy group was achieved with NaBH₄. The reaction of some compounds containing a phenolic hydroxyl with 4-toluenesulfonyl chloride or benzyl bromide in the presence of NaOH led to tosylated or benzylated derivatives. The tosylation or benzylation at the alcoholic hydroxyl was carried out in the presence of sodium metal. Some of the newly synthesized compounds revealed an antimicrobial activity; 6 of 14 new compounds that were studied by the National Cancer Institute were found to possess antitumor activity.__________Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 4, 2005, pp. 430–440.Original Russian Text Copyright ¢ 2005 by N. Demirbas, A. Demirbas, Karaoglu.The text was submitted by the authors in English.     

Design,Synthesis, and Fungicidal Activities of Indole-Modified Cinnamamide Derivatives

Dimethomorph is a kind of cinnamamide fungicide with high fungicidal activities for oomycete diseases. The commercially available dimethomorph is a mixture of two isomers, in which (Z)-dimethomorph possessing higher activity and (E)-dimethomorph possessing lower activity. Herein, we reported the design, synthesis and fungicidal activities of a series of novel indole-modified cinnamamide derivatives, which used the indole group to ‘fix’ the cis-styrene group in (Z)-dimethomorph. The modification of the molecular structure of cinnamamide compounds could be beneficial to improve its practical application performance. Tested the fungicidal activities, it was found that compounds 8j , 9a , 9e , 9i and 9j showed excellent in vivo fungicidal activities (80–100 %) against Pseudoperonospora cubensis at a concentration of 100 mg L⁻¹, while dimethomorph and flumorph were noneffective. Moreover, parts of synthesized indole-modified cinnamamide derivatives 8 ( 8a , 8c , 8d and 8j ) and 9 ( 9c and 9j ) exhibited the same in vivo fungicidal activities against Phytophthora infestans with dimethomorph or flumorph at a concentration of 50 mg L⁻¹ with 100 % inhibition. The biological assay results indicated that indole-modified cinnamamide derivatives have promising applications in the prevention and treatment of Phytophthora infestans.     

Synthesis and Antifungal Activities of Trichodermin Derivatives as Fungicides on Rice

Twenty new trichodermin derivatives, 2a – 5 , containing alkoxy, acyloxy, and Br groups in 4‐, 8‐, 9‐, 10‐ and 16‐positions were synthesized and characterized. The antifungal activities of the new compounds against rice false smut (Ustilaginoidea virens), rice sheath blight (Rhizoctonia solani), and rice blast (Magnaporthe grisea) were evaluated. The results of bioassays indicated that the antifungal activities were particularly susceptible to changes at 4‐, 8‐, and 16‐positions, but low to changes at 9‐ and 10‐positions. Most of these target compounds exhibited good antifungal activities at the concentration of 50 mg l^?1. Compound 4 (9‐formyltrichodermin; EC₅₀ 0.80 mg l^?1) with an CHO group at 9‐position displayed nearly the same level of antifungal activity against Ustilaginoidea virens as the commercial fungicide prochloraz (EC₅₀ 0.82 mg l^?1), while compound 3f ((8R)‐8‐{[(E)‐3‐phenylprop‐2‐enoyl]oxy}trichodermin; EC₅₀ 3.58 and 0.74 mg l^?1) with a cinnamyloxy group at C(8) exhibited much higher antifungal activities against Rhizoctonia solani and Magnaporthe grisea than the commercial fungicides prochloraz (EC₅₀ 0.96 mg l^?1) and propiconazole (EC₅₀ 5.92 mg l^?1), respectively. These data reveal that compounds 3f and 4 possess high antifungal activities and may serve as lead compounds for the development of fungicides in the future.