Synthesis and anti-HIV activity of pyrrolo-[1,2-d]-(1,4)-benzodiazepin-6-ones

The synthesis of novel pyrrolo annulated 1,4-benzodiazepines is described. These pyrrolo[1,2-d]-(1,4)-benzodiazepines have been found to have antiviral activity against HIV-1. Like other non nucleoside HIV-1 RT inhibitors, these compounds appear to be specific for HIV-1.     

Synthesis and anti-HIV properties of new water-soluble bis-functionalized[60]fullerene derivatives

A new series of bis-functionalized fullerene C₆₀ derivatives bearing two or more solubilizing chains have been evaluated for their activity against HIV-1 and HIV-2 strains. Some of the compounds show activity against HIV-1 type in the low micromolar range. The effect of the positions of the addends on the C₆₀ nucleus has been investigated, indicating that only trans-2 isomers possess promising activity. The presence of a quaternary pyrrolidinium nitrogen is essential to increase solubility.     

Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors

A novel series of naphthyl phenyl ether analogues (NPEs) have been synthesized and evaluated for their in vitro activities against HIV in C8166 cells. Most of the compounds exhibited moderate to excellent anti-HIV activities. Among them the most active compound 12o showed excellent activities against wild-type HIV-1 with an EC(50) value of 4.60 nM, along with moderate activities against the double mutant strain HIV-1(IIIB) A17 (K103N+Y181C) and HIV-2 strain ROD with an EC(50) value of 0.82 and 4.40 μM, respectively. Preliminary structure-activity relationship (SAR) among the newly synthesized NPEs was also investigated.     

Synthesis and antiviral activities of enantiomeric 1-[2-(hydroxymethyl) cyclopropyl] methyl nucleosides

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100 microM.     

Design and synthesis of sulfoximine based inhibitors for HIV-1 protease

A new class of potent sulfoximine inhibitors for HIV-1 protease has been designed and synthesized. Substitution of the sulfoximine moiety into different parent compounds yields different inhibition effects. While our previously studied sulfoximine-based inhibitors display potency of 2.5 nM (IC(50)) against HIV-1 protease, introduction of the sulfoximine moiety into the asymmetric Indinavir yielded only micromolar inhibition. Docking studies showed structural variations in their modes of binding which explains this unexpected observation. The implication of these observations in the development of other sulfoximine inhibitors is discussed.     

A fast and robust 19F NMR-based method for finding new HIV-1 protease inhibitors

The human immunodeficiency virus (HIV) which encodes, among other indispensable enzymes, an aspartic protease that is essential for viral maturation and replication. Numerous inhibitors of the protease have been developed. However, the eventual resistance of HIV-1 to these drugs implies a continuous battle to develop new inhibitors. Proposed herein is a robust, fast, and reliable method employing (19)F NMR for the evaluation of the inhibitory activity of new compounds against HIV-1 protease.     

Identification of phytoconstituents from Albizia lebbeck as potential therapeutics against HIV-1 reverse transcriptase associated with infective endocarditis: In silico and in vitro approaches

Acquired immune deficiency syndrome (AIDS) is an unadorned disease affected via the human immunodeficiency virus (HIV), which has become the most infectious diseases worldwide. HIV-1 RT has been shown to be present in the cardiac tissue of patients with HIV-associated infective endocarditis, and to be associated with the development of valvular lesions and other cardiac abnormalities. The use of anti-retroviral therapies has helped to control the virus and reduce the incidence of HIV-1 associated infective endocarditis. Though, these treatments have several adjacent effects, and the improvement of drug-resistant stresses of the virus has become a significant challenge in HIV treatment. This study is to identify A. lebbeck phytoconstituents with HIV-1 RT inhibitory activity for potential therapeutic use against HIV-1 RT associated with infective endocarditis. We performed in silico and in vitro screening of natural cardiovascular phytoconstituents from Albizia lebbeck, a medicinal plant that has been traditionally used for the management of numerous diseases. The in silico results showed that all three compounds (geraldone, luteolin, and isookanin) exhibited affinities of solid binidng to the active amino acids of HIV-1 RT's DNA-polymerase (DNA-p) and Ribonuclease-H (RNA-H) active positions, suggesting their potential as HIV-1 RT inhibitors. In vitro assessment of the three compounds at a concentration of 1 mg/mL revealed that Geraldone exhibited the most effective inhibitory consequence on HIV-1 RT activity (83.45%), followed by Isookanin (75.88%) and Luteolin (66.36%). These findings suggest that these compounds have the potential to inhibit HIV-1 RT associated with infective endocarditis and could assist as main compounds for emerging unique anti-HIV-1 agents. Further studies are needed to confirm the in vitro and in vivo efficacy of these molecules and assess their safety and efficiency as anti-HIV-1 drugs.     

Synthesis and biological evaluation of substituted quinolines: potential treatment of protozoal and retroviral co-infections

We report the synthesis of substituted quinolines and their in vitro biological evaluation against the causal agents of cutaneous leishmaniasis, visceral leishmaniasis, African trypanosomiasis and Chagas' disease. Furthermore, several quinolines have also been tested for their anti-retroviral activity in HIV-1 infected cells. The structure-activity relationships of these new synthetic compounds are discussed and emphasis was placed on the treatment of leishmania/HIV co-infections.     

Synthesis of 1,2,3-triazolo-carbanucleoside analogues of ribavirin targeting an HCV in replicon

The synthesis of carbocyclic and phosphonocarbocyclic analogues of ribavirin, an anti-HCV inhibitor, are described. Those compounds were evaluated against HCV but also against other important viruses in order to determine their spectrum of antiviral activity. Compounds 6 and 13 displayed a moderate IC(50) against HIV-1 of 43.8 and 37 microM, respectively.     

Synthesis and biological activities of new carbaacyclonucleosides and 1'-oxaacyclonucleosides related to clitocine

We describe the synthesis of two series of acyclonucleosides:carbaacyclonucleosides and 1'-oxaacyclonucleosides which possess the same aglycone as clitocine 3 which is a natural nucleoside exhibiting interesting biological properties. These compounds have been obtained by condensation of 4-aminobutanol or 3-silyloxypropoxyamine with 4,6-dichloro-5-nitropyrimidine. Structural modifications have been made on the heterocyclic base and the side chain to enhance their potential activity. All these compounds have been tested against different viruses: HIV-1, HSV-1, HSV-2, CMV, VZV, EBV. The carbaacyclonucleoside 10 was associated with an anti-EBV activity (EC50 = 0.86 microg/mL).     

Ferrocenyl chalcone difluoridoborates inhibit HIV-1 integrase and display low activity towards cancer and endothelial cells

We report here the discovery of a potent series of HIV-1 integrase (IN) inhibitors based on the ferrocenyl chalcone difluoridoborate structure. Ten new compounds have been synthesized and were generally found to have similar inhibitory activities against the IN 3' processing and strand transfer (ST) processes. IC(50) values were found to be in the low micromolar range, and significantly lower than those found for the non-coordinated ferrocenyl chalcones and other ferrocene molecules. The ferrocenyl chalcone difluoridoborates furthermore exhibited low cytotoxicity against cancer cells and low morphological activity against epithelial cells.     

Interaction of ganoderic acid on HIV related target: molecular docking studies

Finding the ultimate HIV cure remain a challenging tasks for decades. Various active compounds have been tested against various components of the virus in the effort to halt the virus development in infected host. The idea of finding cure from known pharmacologically active natural occurring compounds is intriguing and practical. Ganoderma lucidum (Ling-Zhi or Reishi) is one of the most productive and pharmacologically active compounds found in Asian countries. It has been used traditionally for many years throughout different cultures. More than a decade ago, el-Mekkawy and co-workers (1998) have tested several active compounds found in this plant. They have successfully identified several active compounds with reasonable inhibitory activity against HIV protease however; no further studies were done on these compounds. This study aimed to elucidate interactions for one of the active compounds of Ganoderma lucidum namely ganoderic acid with HIV-1 protease using molecular docking simulation. This study revealed four hydrogen bonds formed between model34 of ganoderic acid B and 1HVR. Hydrogen bonds in 1HVR-Model34 complex were formed through ILE50, ILE50', ASP29 and ASP30 residues. Interestingly similar interactions were also observed in the native ligand in 1HVR. Furthermore, interactions involving ILE50 and ILE50' residues have been previously identified to play central roles in HIV-1 protease-ligand interactions.These observed interactions not only suggested HIV-1 protease in general is a suitable target for ganoderic acid B, they also indicated a huge potential for HIV drug discovery based on this compound.     

Design of a "microbicide" for prevention of sexually transmitted diseases using "inactive" pharmaceutical excipients.

The human immunodeficiency virus (HIV-1) pandemic has been driven primarily by the sexual transmission of the virus, and facilitated by prior infections with other sexually transmitted disease (STD) pathogens. Although treatment of these STDs has been proposed as a means to decrease the rate of HIV-1 sexual transmission, preventive measures effective against both HIV-1 and other STD pathogens are expected to have a larger impact. These measures include topically applied mechanical and chemical (i.e. microbicidal) barriers. Microbicides of preference should have a broad specificity against diverse STD pathogens and a well established safety record, considering their repeated use over decades. Here, we report that cellulose acetate phthalate (CAP), an "inactive" pharmaceutical excipient, commonly used in the production of enteric tablets and capsules: (1) has antiviral activity against HIV-1 and several herpesviruses (HSV); and (2) when appropriately formulated, in micronized form, inactivates HIV-1, HSV-1, HSV-2, cytomegalovirus, Neisseria gonorrhoeae, Trichomonas vaginalis, Haemophilus ducreyi and Chlamydia trachomatis but does not affect Lactobacilli, components of the natural vaginal flora contributing to resistance against STDs. Thus, the CAP formulations meet the criteria for preferred microbicides and warrant further evaluation in vivo in humans.     

New sulphonamide and carboxamide derivatives of acyclic C-nucleosides of triazolo-thiadiazole and the thiadiazine analogues. Synthesis, anti-HIV, and antitumor activities. Part 2

A new series of acyclic C-nucleosides 1',2'-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5-8) and arylcarboxamide (9-12) residues have been synthesized under microwave irradiation. Thiadiazines 13-15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16-18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was also screened against a panel of tumor cell lines consisting of CD4 human T-cells.