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A unique prenylated bicarbazole alkaloid, clausanisumine (1), and two biogenetically related known monomer carbazole alkaloids, mukonal (2) and 3-methylcarbazole (3), were isolated from the fruits of Clausena anisum-olens. Clausanisumine (1) was an uncommon prenylated bicarbazole alkaloid, possessing an unprecedented carbon skeleton, which was composed of a simple carbazole alkaloid and a prenylated carbazole alkaloid. The chemical structure of 1 was established by a combination of comprehensive spectral methods. A plausible biosynthetic pathway of 1 was also proposed. Additionally, the potential anti-HIV activities of all isolates 1-3in vitro were evaluated. Compound 1 exhibited remarkable anti-HIV-1 reverse transcriptase effects showing an EC50 value of 18.58 nM. The discovery of the prenylated bicarbazole alkaloid from C. anisum-olens with notable anti-HIV activity would be meaningful to discovering and developing new anti-HIV drugs.

A pair of new oxindole alkaloids, named macrophyllines C (1) and D (2), together with two known oxindole alkaloids isorhynchophylline (3) and corynoxine (4) were isolated from Uncaria macrophylla. Their structures were elucidated based on detailed spectroscopic analysis and by comparison with literature data. In addition, all the isolates were tested for their anti-HIV activities and cytotoxicities in C8166 cells and compounds 2-4 showed weak anti-HIV activities with EC50 values of 11.31 ± 3.29 μM, 18.77 ± 6.14 μM and 30.02 ± 3.73 μM, respectively.

A new icetexane diterpenoid, 11, 12, 20α-trihydroxyl-7β-methoxyicetexa-8, 11, 13-triene-19, 10-lactone [Phyllane A (1)], and a new abietane diterpenoid, 7β, 20-epoxy-3β, 17-acetoxy-abieta-8, 11, 13...

A new method for the synthesis of glycyrrhizic acid (GA) conjugates with S-benzyl-L-cysteine using 1-ethyl-3-(3-dimethylaminoproopyl)carbodiimide is proposed. It is established that 3-O-{2-O-[N-(β-D-glucopyranosyluronyl)-L-cysteine-S-benzyl]-N-(β-D-glucopyranosyluronyl)-L-cysteine-S-benzyl}-(3β,20β)-11-oxo-30-(N-carbonyl-L-cysteine-S-benzyl)-30-norolean-12-ene is superior to GA in inhibiting the accumulation of HIV-I virus-specific protein p24 (viral antigen) in MT-4 cell culture (IC50 3 μg/mL, SI 90) and is 50 - 55 times less toxic to cells than azidothymidine.

Предложен новый способ синтеза конъюгатов глицирризиновой кислоты (ГК) с S-бензил-L-цистеином с использованием 1-этил-3-(3-диметиламинопропил)карбодиимида. Установлено, что 3-О-{2-О-[N-(β-D-глюкопиранозилуроноил)-L-цистеин-S-бензил]-N-(β-D-глюкопиранозилуроноил)-L-цистеин-S-бензил}-(3β,20β)-11-оксо-30-(N-карбонил-L- цистеин-S-бензил)-30-норолеан-12-ен превосходит ГК по ингибированию накопления вирусоспецифического белка р24 (вирусного антигена) ВИЧ-1 в культуре клеток МТ-4 (IC50 3 мкг/мл, SI 90) и является в 50 – 55 раз менее токсичным веществом для клеток, чем азидотимидин.

We report the synthesis of phosphoramidate conjugates of 3′-azido-3′-deoxythymidine (AZT) glycerolipid derivatives and amino acid esters. For the synthesized compounds, 50% inhibition of the HIV-1 MvP-899 strain in human T lymphoid MT-4 cells is achieved at concentrations of 0.014–0.356 µM. Significantly, compound 3c (which contained ethyl ester of α-alanine) was found to be the most active with EC50 value 0.014 µM. We show that, among these glycerolipid derivatives of AZT, some compounds are less toxic than AZT, and also they possess a similar or higher selectivity index compared to AZT (SI = 11643).

Five new [daphneodorins D–H (1, 5, and 10–12)] and seven known daphnane diterpenoids (2–4 and 6–9) were isolated from Daphne odora. The structures of the new compounds were elucidated by extensive physicochemical and spectroscopic analysis. The isolated compounds were evaluated for their anti-HIV activity against HIV-1 infection of MT4 cells. Nine daphnane diterpenoid orthoesters (1–9) showed potent anti-HIV activity with EC(50) values of 1.5–7.7 nM.

Summary Acquired immunodeficiency syndrome (AIDS) is an immunosuppressive disease caused by human immunodeficiency virus (HIV). The urgent need for searching novel anti-HIV/AIDS medicines is a global concern. So far, a lot of medicinal and aromatic plants (MAPs) have been analyzed to select those that could assist in the prevention and/or amelioration of the disease. Among biologically active compounds present in these plants, one of the most promising group are phenolics. The purpose of this article was to report anti-HIV activity of selected phenolic compounds of plant origin.

In the last 2-3 decades, the broad research in the application of benzimidazole derivatives made it important for mankind. Many scientists have worked on benzimidazole derivatives and they found that this compound has a diverse role in the field of medicinal chemistry. Few benzimidazole derivatives are currently in the market as a drug candidate against various diseases. Moreover, the benzimidazole derivatives exhibit pharmacological activities such as anti-tuberculosis, anti-malarial, antihistamine, antimicrobial, antiviral, antidiabetic, anticancer, anti-fungal, anti-inflammatory, analgesic, anti-HIV, etc. In this review, we have summarized various derivatives of benzimidazole which have been prepared by many researchers to understand the chemistry as well as diverse pharmacological activities. These findings may lead the scientists who are working in the field of medicinal chemistry to the development of benzimidazole based drug candidates in the future.

The similarity is an important category in natural sciences. A measure of similarity for a group of various biochemical endpoints is suggested. The list of examined endpoints contains (1) toxicity of pesticides towards rainbow trout; (2) human skin sensitization; (3) mutagenicity; (4) toxicity of psychotropic drugs; and (5) anti HIV activity. Further applying and evolution of the suggested approach is discussed. In particular, the conception of the similarity (dissimilarity) of endpoints can play the role of a “useful bridge” between quantitative structure property/activity relationships (QSPRs/QSARs) and read-across technique.

An expansion of the structure-activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays. ispartof: MOLECULES vol:26 issue:20 ispartof: location:Switzerland status: published

AIDS, caused by HIV-1, is one of the most dangerous infectious diseases in the world. Therefore, it is necessary to develop new drugs with more potent bioactivities, less toxicity and higher tolerability for controlling the viral load, particularly by using the raw materials that are widely available. Agaricus blazei Murill (AbM), known in China as jisongrong, is of great importance as a food source and as a health-promoting supplement for immunomodulation. The polysaccharides of AbM exhibit various biological activities, such as regulating cellular immunity and providing anti-oxidative, anti-infective, and anti-inflammatory effects. At present, to our knowledge, no report has explored the chemically sulfated and anti-HIV-1 activity of AbM polysaccharides. Herein, the sulfated AbM polysaccharides with different sulfur contents were prepared by the chlorosulfonic acid-pyridine method. The characteristics of sulfated derivatives were established by the determination of the sulfur content, the relative molecular weight, and the Fourier-transform infrared spectroscopy. The anti-HIV activities of the sulfated AbM polysaccharides were evaluated by CCK-8 and the single-cycle pseudovirus infection (TZM-bl) assay. The sulfated AbM polysaccharides had strong antiviral properties, and the half-maximal inhibitory concentrations approached that of the positive control, azidothymidine. Sulfated modification of AbM polysaccharides can increase their anti-HIV pharmacological activity, which makes them promising alternative candidates as bioactive macromolecules for biomedical applications in HIV/AIDS.

We have systematically investigated the chemical constituents of E. lathyris from Hebei Province. Consequently, a new ingenane-type diterpenoid (1) was isolated, together with 17 known diterpenoids (2–18). The structures of these compounds were established by NMR spectra and comparison with the literature. The anti-HIV activity of ethanol extracts of the seeds of Euphorbia lathyris from different origins was evaluated. The results showed that all the ethanol extracts exhibited significant anti-HIV activity. The anti-HIV activity of the 18 compounds was determined, but all of the compounds were inactive against HIV viral replication.

Based on the potent anti-HIV activity of L-2',3'-dideoxycytidine (L-ddC), L-2',3'-dideoxy-4'-selenonucleosides (L-4'-Se-ddNs) have been synthesized from natural chiral template, L-glutamic acid, using Pummerer-type condensation as a key step. All synthesized compounds were assayed for anti-HIV-1 activity, but none of them did show any significant antiviral activity up to 100 μM, probably due to conformational differences between L-ddC and L-4'-Se-ddC, induced by the bulky selenium atom, which might play an important role in phosphorylation by cellular kinase.

A series of fifteen new 2-[3-(3-chlorophenyl)-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(2H)-yl]-N′-arylmethyleneacetohydrazides (5a–o) were synthesized and screened for their anti-HIV-1 and cytotoxicity activity. Out of fifteen pyrazolobenzothiazine-based hydrazones, thirteen were found to be active inhibitors of HIV with EC(50) values

Supplemental Digital Content is Available in the Text., Objective: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR). Design: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days. Methods: TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTC-triphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1BaL. Results: Adverse events (AEs) were more common with oral TDF/FTC use (P < 0.01). The median CVF TFV concentrations were 106 ng/mL after use of TFV IVR vs. 102 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were >100-fold higher among IVR users. The median CVF FTC concentrations were 103 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P < 0.01) but was higher in TFV IVR users (P < 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 µg/mL TFV, 1 µg/mL FTC, and 0.1 µg/mL of TFV and FTC combined. Conclusions: Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.

BACKGROUND: Lycium barbarum polysaccharides (LBPs) belong to a very important class of biological macromolecules from Lycium barbarum berries in nature, and have received much attention due to their various biological activities. Since sulfated polysaccharides have antiviral activity in vitro, there is no published research on the sulfated modification of LBPs. RESULTS: The objective of this study was to investigate the feasibility of sulfated modification of LBPs and their potential application in inhibiting HIV-1. The LBPs with different molecular weight were prepared by fractional precipitation from crude LBP through aqueous extraction, ethanol precipitation and deproteinization. The purified LBPs (G1, G2 and G3) were sulfated by chlorosulfonic acid pyridine method to give rise to the sulfated LBPs (G1S1-G1S4, G2S1-G2S4 and G3S1-G3S4) with different degrees of substitution. The anti-HIV-1activities were evaluated by TD50 of the cytotoxicity and IC50 of inhibitory activity using the CCK-8 and Magi test with Azidothymidine (AZT) as positive control. The results showed that LBPs and sulfated LBPs showed non-toxicity with the TD50 >100 μg/mL. Compared with the LBPs, the inhibition of anti-HIV-1 activity of sulfated LBPs was increased significantly with the IC50 value from 0.0924-0.1206 μg/mL to 0.0206-0.0722 μg/mL. The G1S4 (Mw=2.13×104 Da and DS=1.12) showed excellent anti-HIV-1 activity with the IC50 value near to that of AZT (0.0200μg/mL), which would make it possible to become a candidate compound with anti-HIV-1 activity.CONCLUSION: The outcome of the study indicated that sulfated modification of LBPs was feasible and sulfated LBPs had good potential as an anti-HIV drug.

Six dibenzo-1,4-dioxane derivatives (1–6) were isolated from the roots of a Hypericaceous plant Hypericum ascyron. Spectroscopic analyses revealed 2 and 4–6 to be new compounds. The partial racemic natures of 1–3 were concluded by chiral HPLC analyses, while 5 was confirmed to be a racemate. The absolute configurations 1–4 were deduced on the basis of ECD calculations. Biological activity evaluation of the dibenzo-1,4-dioxane derivatives along with two related compounds: hyperdioxanes A (7) and B (8), previously isolated from the same plant material by our group demonstrated that 7 exhibit an anti-HIV activity (IC50 5.3 μM, TI 7.2) while 8 showed an inhibitory effect on IL-1β production (inhibition rate: 72.3% at 6.3 μM) from LPS-stimulated microglial cells.

[Image: see text] Novel betulinic/betulonic acid–nucleoside hybrids were synthesized as possible new anti-HIV agents. Among the synthesized hybrids, two compounds were highly effective against HIV. Compared with AZT and DSB, compounds 10a (IC(50) = 0.0078 μM, CC(50) = 9.6 μM) and 10b (IC(50) = 0.020 μM, CC(50) = 23.8 μM) showed more potent or equipotent, respectively, anti-HIV activity but displayed lower cytotoxicity.

Anti retroviral drugs for HIV has problems with uncomfortable side effects and that endanger the lives of HIV sufferers. Several herbs have been empirically proven to have an effect on HIV eradication through inhibition of reverse transcriptase. One of such antiviral herbs is Justicia gendarussa (J. gendarussa). The aim of research is to evaluate anti-HIV activity of 70% fractionated-ethanol extract (with releasing alkaloids) and 70% ethanol extract (without releasing alkaloids) of J. gendarussa leaves on in vitro HIV-infected of MOLT-4 cells. The effect of the extracts in inhibiting viral replication and fusion process on acute HIV infection was identi- fied through syncytia formation assay. Effect of the extracts on HIV p24 antigen was evaluated using HIV-1 p24 ELISA kit. It was found that 70% fractionated-ethanol extract and 70% ethanol extract of J. gendarussa leaves significantly inhibited of HIV replication by inhibition of syncytia formation, where the 50% effective concen- tration (EC50) values of the 70% fractionated-ethanol extract and 70% ethanol extract are 70.5 μg/mL and 228.7 μg/mL, respec- tively. Both of the extracts were also significantly inhibited HIV replication by decreasing HIV p24 antigen level where the EC 50 values of the 70% fractionated-ethanol extract and 70% ethanol extract are 88.8 μg/mL and 540.7 μg/mL, respectively. Moreover, it was found that 70% fractionated-ethanol extract of J. gendarussa leaves has anti-HIV activity since its EC50 values less than 100 μg/mL. It was concluded that J. gendarussa could be potentially developed into a phytopharmaceutical product due to its anti-HIV activity.

BACKGROUND The development of severe drug resistance caused by the extensive use of anti-HIV agents has resulted in a greatly extensive reduction in these drugs efficacy. OBJECTIVES To identify the important pharmacophoric features and correlate 3D chemical structure of benzothiazinimines with their anti-HIV potential using 2D, 3D-QSAR and pharmacophore modeling studies. METHODS QSAR and pharmacophore mapping studies have been used to relate structural features. 2D QSAR and 3D QSAR studies were performed using partial least square and k-nearest neighbor methodology, coupled with various feature selection methods, viz. stepwise, genetic algorithm, and simulated annealing, to derive QSAR models which were further validated for statistical significance. RESULTS The physicochemical descriptor XAHydrophilicArea and SsOHE-index, and alignmentindependent descriptor T_C_Cl_6 showed significant correlation with the anti-HIV activity of benzothiazinimines in 2D QSAR. 3D QSAR results showed the significant effect of electrostatic and steric field descriptors in the anti-HIV potential of benzothiazinimines. The generated pharmacophore hypothesis demonstrated the importance of aromaticity and hydrogen bond acceptors. CONCLUSION The significant models obtained in this study suggested that these techniques could be used as a guidance for designing new benzothiazinimines with enhanced anti-HIV potential.

Background T-705 (Favipiravir) is a broad spectrum antiviral agent approved for stockpiling in Japan and currently in Phase 3 testing in the United States. Against influenza, it acts as a prodrug, converted intracellularly to selectively inhibit viral RNA-dependent RNA polymerase or similar enzymes. This is regarded as a novel antiviral mechanism of action, reducing crossresistance to other existing anti-influenza drugs. Objective To develop new analogs, a class of 1,3-oxathiolane nucleoside derivatives of T-705 was designed and synthesized in this work. Results Anti-influenza activity and Anti-HIV activity of these compounds were evaluated. Compound 1a displayed activity against A H1N1 with an IC50 of 40.4 µmol/L. Compound 1b showed weak activity against HIV with a viral suppression rate of 70-80% at 30 µmol/L. Conclusion A class of 1,3-oxathiolane nucleoside derivatives of T-705 was designed and synthesized, and one of them was identified as a novel scaffold against viral infection.

Firstly discovered in 1980s, human immunodeficiency virus (HIV) continues to affect more and more people. However, there is no effective drug available for the therapy of HIV infection. Betulinic acid existing in various medicinal herbs and fruits exhibits multiple biological effects, especially its outstanding anti-HIV activity, which has drawn the attentions of many pharmacists. Among the derivatives of betulinic acid, some compounds exhibited inhibitory activities at the nanomolar concentration, and have entered phase II clinical trials. This paper summarizes the current investigations on the anti-HIV activity of betulinic acid analogues, and provides valuable data for subsequent researches.

Twenty-three new C21 steroidal glycosides, marstenacissides C1–C10 (1–10), D1–D7 (11–17) and E1–E6 (18–23), and four new C21 steroids, 11α,12β-O-ditigloyl-tenacigenin C (24), 11α-O-benzoyl-12β-O-tigloyl-tenacigenin C (25), 11α-O-tigloyl-12β-O-benzoyl-tenacigenin C (26) and 11α-O-tigloyl-12β-O-benzoyl-marsdenin (27), were isolated from the Dai herbal medicine Dai-Bai-Jie, derived from the roots of Marsdenia tenacissima. The chemical structures of all compounds were established by spectroscopic techniques, including high-resolution mass spectrometry and NMR spectroscopy, as well as by comparison with reported spectral data. The anti-HIV activities of these compounds were screened, and the compounds obtained displayed inhibitory effects against HIV-1 with inhibition rates of 36.4–81.3% at 30 μM.

This article describes the Quantitative structure–activity relationship models of 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine inhibition of the human immunodeficiency virus (HIV-1) reverse transcriptase (RT) was developed using the multi linear regressions method. These studies were performed using 60 compounds with the help of quantum descriptors as Ionization Potential, Electron Affinity, Softness, global Electrophilicity index and Fukui functions. These indices are obtained at the DFT/B3LYP level of quantum calculation. The statistical quality of the QSAR models was assessed using statistical parameters R2. Good agreements between experimental and calculated log1/EC50 values of anti-HIV activity were obtained. Four QSAR models are presented and the best one use nine molecular quantum descriptors.

The human immunodeficiency virus type 1 (HIV-1) is one of the deadliest viruses that affect public health worldwide. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization estimate that there are more than 15 million people infected with this HIV-1 around the world. The cure of HIV-1 and a better understanding of effective drugs are urgently needed. In this work, we study the structure–activity relationship and predict the potency of HIV-1 drug compounds. We employ the random forest technique to select relevant molecular descriptors of 132 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) compounds toward the inhibition of HIV-1 reverse transcriptase (RT). The best model yields 5 relevant descriptors with a coefficient of determination (R 2) of 0.83. Our prediction model suggests that a potent HEPT compound must be a lipophilic molecule with a high value of fractional hydrophobic van der Waals surface areas.

Four new farnesylated isoindolinone derivatives, named stachybotrysams A–D ( 2 – 5 ), and one new farnesyl-cyclized analogue, named stachybotrysam E ( 6 ), as well as one known congener ( 1 ), were isolated from the filamentous fungus Stachybotrys chartarum CGMCC 3.5365. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and by comparison with reported data. Compounds 2–4 exhibited significant HIV-inhibitory activity with IC 50 values of 9.3, 1.0, and 9.6 μ M, respectively.

The development of new HIV non-nucleoside reverse transcriptase inhibitors offers the possibility of generating structures of increased potency. To this end, coupling of mefenamic acid (4) with 4-amino-acetophenone (6) in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP) reagents afforded 4-(acetyphenyl)-2-((2,3-dimethylphenyl)amino)benzamide (7). Analogously, treatment of mefenamyl chloride (5) prepared from 4 with 6 under microwave irradiation (MWI) afforded 7. A new series of substituted chalconyl-incorporated amide derivatives of mefenamic acid 8–13 were synthesized from condensation of 7 with various substituted benzaldehydes via the Claisen–Schmidt reaction. Treatment of 8 and 11 with thiourea in a basic medium afforded the thiopyrimidine analogues 14 and 15, respectively. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 9 and 11 showed cytotoxicity values of 2.17 and 2.06 μm, respectively, against mock-infected MT-4 cells (C type adult T leukemia cells), which considered to be promising antileukemic agents.

Nearly four decades have passed since the human immunodeficiency virus (HIV) was discovered as the causal agent of acquired immune deficiency syndrome (AIDS). Nevertheless, HIV continues to cause substantial morbidity and mortality, posing a formidable challenge to public health scenario all over the world. Globally, 36.9 million people were living with HIV at the end of 2017, with a burden of 1.8 million new cases added every year. In the meantime, the introduction of highly active antiretroviral therapy (HAART) could dramatically change the prognosis of HIV infection from high mortality to chronic illness. However, apart from the high cost and drug-induced toxicity, HAART in the long-term leads to the emergence of multidrug-resistant strains, which would surpass the rate of new drug development. Therefore, it is a challenge to discover safe and cost-effective drugs at the earliest, with the aim to hit specific targets in the HIV life cycle. Natural products, since time immemorial, serve as a prospective resource for the development of novel therapeutic agents. Many traditional medicinal plants exhibited anti-HIV activity, and a few of them were reportedly used for the management of HIV infections. Plants like Echinacea purpurea, Moringa oleifera, and Tripterygium wilfordii have undergone clinical trials for anti-HIV therapy. Quite a few phytochemicals like andrographolide, calanolide A, mangiferin, 3-O-(3′,3′-dimethylsuccinyl), betulinic acid (PA-457) are expected to play promising roles in future. Presently, we compiled recent findings on novel plant-derived products showing activity against HIV, along with putative mechanisms of action. Mainly, up-to-date information on target-based strategies to identify anti-HIV plant constituents will be presented in this chapter.

Marine sponges are considered as an untapped reservoir of biologically active natural compounds exhibiting numerous interesting and potentially useful pharmacological activities, including antimicrobial, antifungal, cytotoxic, anti-inflammatory, and immunostimulatory activities. One class of such compounds is the cyclic depsipeptides, which are characterized by the incorporation of at least one ester linkage into their structures. Callipeltin A and its 14 analogs, neamphamide A, papuamides A and B, pipecolidepsin A and 10 homophymines are cyclic depsipeptides isolated from marine sponges, have structurally unique features incorporating several modified amino acid residues, and are well known for their potent HIV-inhibitory activity. A variety of synthetic studies have been undertaken, to elucidate the motifs essential for biological activity and meet the challenge posted by their synthesis. In this chapter, recent progress in the isolation and synthesis of the callipeltins will be reviewed.

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol-thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.

Novel 4′-C-ethynyl isomeric dioxolane nucleoside analogues (β- d , α- d , β- l , and α- l , respectively) are successfully synthesized via a divergent strategy from the common starting material, (Z)-but-2-ene-1,4-diol, and are characterized and evaluated for their anti-HIV-1 and anti-HIV-2 activities. The β- d and β- l products display potent in vitro activities against HIV-1 (IIIB) with EC50 values of 0.75 and 0.87 μM, respectively, and against HIV-2 (ROD) with EC50 values of 0.75 and 0.35 μM, respectively, being better in comparison with 3TC [EC50, 5.27 μM (HIV-1) and 1.30 μM (HIV-2)]. The β- d and β- l nucleosides also potently inhibit different drug-resistant strains of the HIV-1 virus (L100I, K103N, Y181C, and V106A). The selectivity indices and cytotoxic profiles of the β- d and β- l nucleosides are much better than those of the standard drugs AZT and d4T.

On the hypothesis that one carbon homologation of 4′-selenonucleosides might relieve the steric repulsion between cellular kinases and bulky selenium, 5′-homo-4′-Se-d4Ns, 3 a–e, as anti-HIV agents were designed and synthesized stereoselectively from d-gulonic γ-lactone, with the conversion of 2′,3′-diol into the olefin as the key step. The anti-HIV activity of all synthesized compounds, 5′-homo-4′-Se-d4Ns, was toxicity-dependent, unlike normal 4′-Se-d4Ns, which were inactive against HIV-1. This result indicates that 5′-homo-4′-Se-d4Ns might be phosphorylated by cellular kinases as per the hypothesis.

Bioassay-guided fractionation of the n-butanol extract from the branches and leaves of Reutealis trisperma resulted in the isolation of six undescribed (crotignoids L ~ Q) together with two known (12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-myristate) tigliane diterpenoids. Their structures, especially the absolute configurations, were determined from extensive spectroscopic studies, including 2D NMR spectra, CD data analysis and electronic circular dichroism (ECD) calculations. All isolates were tested for anti-HIV activity against HL4-3 virus in MT4 cells. Except for crotignoid Q, the remaining seven tigliane diterpenoids exhibited potent anti-HIV activity with IC50 values ranging from 0.0023 to 4.03 μM.

A new series of mononuclear ruthenium(II) complexes of the type [Ru(PPh3)2(N,S-L1–3)2] 2H3O+.(Cl−)2.XH2O, [RuCl(dmso)3(N,S-L1–3)], and [Ru2(Cl−)2(N,S-L1–3)2].XH2O, where L1 is ethyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-pyrimidine-5-carboxylate (monastrol), and L2 and L3 are the 4-hydroxyphenyl and 4-bromophenyl analogs of monastrol have been prepared and characterized by elemental analysis, 1H, and 13C NMR spectroscopy. All the complexes were assayed for their anti-HIV-1 and HIV-2 activity in MT-4 cells, and cytotoxicity was also investigated in mock-infected in MT-4 cells by using MTT assay. All the complexes exhibited no anti-HIV activity, however complexes [RuCl(dmso)3(N,S-L1)] (7) and [RuCl(dmso)3(N,S-L2)] (8) showed cytotoxicity values of > 0.21 and > 2.14 µM, respectively against mock-infected MT-4 cells. In addition, complexes [Ru(PPh3)2(N,S-L3)2].2H3O+.2Cl−.H2O (4), 7, and [RuCl2(N,S-L1)] (10) have been selected for evaluation of their dual inhibition activity against dual-specificity tyrosine phosphorylation-regulated kinase (Dyrk1A).

We report the preparation and characterization of five new [60]fullerene derivatives formed in the novel reaction of C60Cl6 with dimethyl 2,2′-(1,4-phenylenebis-(oxy))diacetate, which were isolated by preparative HPLC and characterized by APCI-MS, 1H, 13C, and 2D NMR spectroscopy. Acidic hydrolysis of the ester groups in the synthesized compounds produced a series of water-soluble fullerene derivatives, which demonstrated pronounced activities against Human Immunodeficiency Virus (HIV) replication. Correlations between the structures of the fullerene derivatives and their antiviral activity were established.

Human immunodeficiency virus (HIV) remains a worldwide health problem despite huge investments and research breakthroughs, and no single drug is effective in killing the virus yet. Among new strategies to control HIV infection, the phage display (PD) technology has become a promising tool in the discovery of peptides that can be used as new drugs, or also as possible vaccine candidates. This review discusses basic aspects of PD and its use to advance two main objectives related to combating HIV-1 infection: the identification of peptides that inhibit virus replication and the identification of peptides that induce the production of neutralizing antibodies. We will cover the different approaches used for mapping and selection of mimotopes, and discuss the promising results of these biologicals as antiviral agents.

HIV integrase, encoded at the 3′-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of “no-return” in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.

A series of novel 3-aryl-6-adamantylmethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 6a–l were synthesized by a simple method with the aim of developing novel HIV non-nucleoside reverse transcriptase inhibitors. All the synthesized compounds were structurally confirmed by spectral analyses. The structure of 6a was unambiguously verified by X-ray structure determination. The synthesized compounds were evaluated for their anti-HIV activity and four analogs displayed moderate inhibitory activity with EC50 values ranging from 10.10 to 12.40 μg mL–1. Molecular docking of 6g with HIV-1 reverse transcriptase was studied to rationalize some structure-activity relationships (SARs).

A new series of 6-amino-5-(aryldiazenyl)-N 1,N 3-dimethyl-2-thioxo-pyrimidin-4-one derivatives 17–27 and the N 1-methyl-azothiopyrimidine analog 28 were synthesized from the pyrimidine derivatives 4 and 5, respectively, via diazotization reaction, with various amines. The platinum(II) metal complexes [bis(4-amino-N 3-methyl-6-oxo-2-thioxo-pyrimidin-1-yl)]Pt(II) (29) and [(6-amino-5-(4-R-phenyl)diazenyl)-N 1 ,N 3-dimethyl-2-thioxo-pyrimidin-4-one)]Pt(II)Cl2 derivatives 30–33 were prepared from the treatment of 5 and the azo analogs 17 and 21–23 with PtCl2, respectively. Analogously, 5 and 17 were treated with RuCl3·3H2O to give the Ru(III) complexes 34 and 35, respectively. The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. The results revealed that 26 and 30 were the only compounds in the series inhibiting HIV replication in cell cultures with an IC50 value of >2.07 and >3.02 μg mL–1, respectively. The molecular modeling interactions of 26 with some amino acids of HIV reverse transcriptase were studied. In addition, the antibacterial activity of 17–35 and 31–33 against Staphylococcus aureus and Escherichia coli was evaluated.

Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT) inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC50 values ranging of 0.105–14.531 μmol/L. In particular, compound 13f not only has high anti-HIV-1 activity (0.108 μmol/L), but also possesses low toxicity with a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of these analogues may serve as an important clue for further optimizations.

Three new compounds (1 - 3), including two euphane type triterpenes, 24,24-dimethoxy-25,26,27-trinoreuphan-3β-ol (1) and (24S)-24-hydroperoxyeupha-8,25-dien-3β-ol (2), and an ent-atisine diterpene, ent-atisane-3α,16α,17-triol (3), were isolated from an acetone extract of the stems of Euphorbia antiquorum, together with eight known diterpenes (4 - 11). The structures of compounds (1 - 11) were elucidated using NMR and MS spectroscopic methods. Compound 7 showed moderate activity against HIV-1 replication in vitro (EC50 = 1.38 μm).