High anti-HIV Activity Research Articles

The design of compounds with desirable properties - The anti-HIV case study.

Efficacy and safety are among the most desirable characteristics of an ideal drug. The tremendous increase in computing power and the entry of artificial intelligence into the field of computational drug design are accelerating the process of identifying, developing, and optimizing potential drugs. Here, we present novel approach to design new molecules with desired properties. We combined various neural networks and linear regression algorithms to build models for cytotoxicity and anti-HIV activity based on Continual Molecular Interior analysis (CoMIn) and Cinderella's Shoe (CiS) derived molecular descriptors. After validating the reliability of the models, a genetic algorithm was coupled with the Des-Pot Grid algorithm to generate new molecules from a predefined pool of molecular fragments and predict their bioactivity and cytotoxicity. This combination led to the proposal of 16 hit molecules with high anti-HIV activity and low cytotoxicity. The anti-SARS-CoV-2 activity of the hits was predicted.

Biosynthesis and optimization of highly stable gold nanoparticles, nanoconjugates, nanodrug conjugates and chitosan nanoconjugates using medicinal plants

BackgroundIn the present study, the medicinal plants were exclusively selected based on their significant anti-HIV and anticancer activities. The green synthesis of gold nanoparticles was carried out using the 15 medicinal plant extracts on reduction with chloroauric acid. The present study also focused on a novel pharmacognostic approach over the usage of plants source. The nanoparticle synthesized through medicinal plants possessed the potential therapeutic properties of the plants. The resultant nanoparticle carried the attributes of a nanomaterial alongside the phytoactivity.ResultsInitially, individual nanoparticle (NP) was synthesized through a single plant extract and studied for its effective anti-HIV and anticancer activity. Finally, a nanoconjugate (NC) comprising of the 3 extracts (trio extract) in one nanoparticle was synthesized. The nanoparticles which exhibited comparatively high anti-HIV and anticancer activity were chosen for the synthesis of nanoconjugate, thereby achieving a synergistic anticancer and anti-HIV activity. Further, a nanodrug conjugate (NDC) was prepared in combination of AuNPs and the chemotherapeutic drug, doxorubicin (Dox) for cancer and AuNPs with antiretroviral drug azidothymidine (AZT) for HIV.ConclusionsA nanodrug conjugate helps to enhance the efficiency of the drug. The nanodrug conjugate brings about a combinatorial effect of the nanomaterials and the drug. Further, a biocompatible nanocarrier was developed as a conjugate with chitosan and gold nanoparticles using STPP as gelating agent for the drug doxorubicin. The synthesis reaction was optimized under various underlying parameters. The gold nanoparticles proved to be stable at high temperature and different buffers and ensured to be a safe option for bioassays and in vivo applications. Upon storing the synthesized AuNPs at different storage conditions, the nanoparticles were observed to be highly stable for a period of more than 48 months. The present study resulted in biosynthesis of highly stable gold nanoparticles using medicinal plant extracts as reducing and stabilizing agents.

Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors.

CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.

Elucidation of anti-HIV mechanism of sulfated cellobiose–polylysine dendrimers

Three new spherical sulfated cellobiose–polylysine dendrimers of increasing generations bearing negatively charged sulfate groups were prepared by sulfating the corresponding cellobiose–polylysine dendrimers. The first, second, and third-generation derivatives exhibited potent anti-HIV activity with EC50 values of 3.7, 0.6, and 1.5 μg/mL, respectively, in constant to sulfated oligosaccharides with low anti-HIV activity, while the second-generation sulfated dendrimer was the most active. Surface plasmon resonance measurements with poly-l-lysine bearing positively charged amino acids as a model of the HIV surface glycoprotein gp120, indicated that the second-generation dendrimer had the lowest dissociation constant (KD = 1.86 × 10−12 M). Both the particle size and ζ potential increased in the presence of poly-l-lysine. It was proven that the moderate distance between the terminal sulfated cellobiose units in the second-generation dendrimer favored the high anti-HIV activity, owing to the electrostatic interactions developed due to the cluster effect.

Role of a long-chain alkyl group in sulfated alkyl oligosaccharides with high anti-HIV activity revealed by SPR and DLS

Although a long-chain alkyl group in sulfated oligosaccharides can enhance the anti-HIV activity, the exact mechanism is unclear. To elucidate the role of the long-chain alkyl group, its interaction with a liposome (100 nm) as a HIV model was investigated by surface plasmon resonance and dynamic light scattering. The newly synthesized sulfated 1-(decadecyl-1, 2, 3-triazole)-1-deoxy- maltoheptaoside bearing the long-chain alkyl group was found to interact with the liposome. The particle size increased and the ζ potential was negative, indicating that the sulfated alkyl maltoheptaoside was attached to the liposome by the long-chain alkyl group and the fixed sulfated maltoheptaoside moiety was covered on the liposome. Thus, the long-chain alkyl group penetrates and is fixed into the lipid bilayer of HIV and the sulfated maltoheptaose moiety with negatively charged sulfate groups was electrostatically interacted with HIV gp120 molecule with positively charged amino acids to achieve the inhibition of HIV infection.

Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands.

The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5-7.5 Å showed potent binding affinity selective for CXCR4 with IC50 values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC50s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.

Soluble-type small-molecule CD4 mimics as HIV entry inhibitors

Several small molecule CD4 mimics have been reported previously as HIV-1 entry inhibitors, which block the interaction between the Phe43 cavity of HIV-1 gp120 and the host CD4. Known CD4 mimics such as NBD-556 possess significant anti-HIV activity but are less soluble in water, perhaps due to their hydrophobic aromatic ring-containing structures. Compounds with a pyridinyl group in place of the phenyl group in these molecules have been designed and synthesized in an attempt to increase the hydrophilicity. Some of these new CD4 mimics, containing a tetramethylpiperidine ring show significantly higher water solubility than NBD-556 and have high anti-HIV activity and synergistic anti-HIV activity with a neutralizing antibody. The CD4 mimic that has a cyclohexylpiperidine ring and a 6-fluoropyridin-3-yl ring has high anti-HIV activity and no significant cytotoxicity. The present results will be useful in the future design and development of novel soluble-type molecule CD4 mimics.

Recent Progress of Basic Studies of Natural Products and Their Dental Application

The present article reviews the research progress of three major polyphenols (tannins, flavonoids and lignin carbohydrate complexes), chromone (backbone structure of flavonoids) and herbal extracts. Chemical modified chromone derivatives showed highly specific toxicity against human oral squamous cell carcinoma cell lines, with much lower toxicity against human oral keratinocytes, as compared with various anticancer drugs. QSAR analysis suggests the possible correlation between their tumor-specificity and three-dimensional molecular shape. Condensed tannins in the tea extracts inactivated the glucosyltransferase enzymes, involved in the biofilm formation. Lignin-carbohydrate complexes (prepared by alkaline extraction and acid-precipitation) and crude alkaline extract of the leaves of Sasa species (SE, available as an over-the-counter drug) showed much higher anti-HIV activity, than tannins, flavonoids and Japanese traditional medicine (Kampo). Long-term treatment with SE and several Kampo medicines showed an anti-inflammatory and anti-oxidant effects in small size of clinical trials. Although the anti-periodontitis activity of synthetic angiotensin II blockers has been suggested in many papers, natural angiotensin II blockers has not yet been tested for their possible anti-periodontitis activity. There should be still many unknown substances that are useful for treating the oral diseases in the natural kingdom.

Flexibility of small molecular CD4 mimics as HIV entry inhibitors.

CD4 mimics such as YIR-821 and its derivatives are small molecules which inhibit the interaction between the Phe43 cavity of HIV-1 gp120 with host CD4, an interaction that is involved in the entry of HIV to cells. Known CD4 mimics generally possess three structural features, an aromatic ring, an oxalamide linker and a piperidine moiety. We have shown previously that introduction of a cyclohexyl group and a guanidine group into the piperidine moiety and a fluorine atom at the meta-position of the aromatic ring leads to a significant increase in the anti-HIV activity. In the current study, the effects of conformational flexibility were investigated by introduction of an indole-type group in the junction between the oxalamide linker and the aromatic moiety or by replacement of the oxalamide linker with a glycine linker. This led to the development of compounds with high anti-HIV activity, showing the importance of the junction region for the expression of high anti-HIV activity. The present data are expected to be useful in the future design of novel CD4 mimic molecules.

Host-directed broad-spectrum antiviral drugs

Viruses completely depend on cellular factors to multiply. In spite of their unique coding features, different viruses are shown to depend upon some common host factors. Consequently, it should be possible to develop broad-spectrum antivirals by targeting them. In the presentation, the author will give an summary of the concept of host-targeting, broad-spectrum antiviral drugs and our work on natural products. The author will specially specialise in metabolites isolated from myxobacteria, one among the highest producers of natural products with host-targeting properties. With viral infections this is not possible. There are currently very few antiviral drugs and those that exist are specific to one type of virus, requiring a diagnostic process before being able to apply treatment. The development of broad-spectrum antivirals would speed up the prescription of treatments, which in many cases, is essential to beat the disease, and would provide a first line of defence against new viruses. "Antiviral drugs on the market today are aimed at specific components of a virus, usually viral enzymes necessary for the multiplication of the virus in infected cells", explains Georgios Koutsoudakis, researcher of Juana Diez's group and first author of the study. Bearing in mind that viruses of different families are genetically quite different, direct action antivirals are tailored to a specific type of virus. Moreover, its potential as an inhibitor of HCV is just as good as an anti-HCV drug already present on the market. This compound is SoraphenA, a product extracted from soil myxobacteria that is targeted at the cellular enzyme Acetyl-Coenzyme A Carboxylase (ACC), a protein involved in the synthesis of lipids within cells. The great advantage of this compound is that because its antiviral activity is mediated by a cell component, it is effective for various genotypes of HCV and is little susceptible to developing drug resistance. Given that not only HIV and HCV but many other viruses, including the emerging Dengue virus, West Nile virus and Chikungunya virus, depend on the lipid cellular metabolism to multiply, it is possible that the antiviral activity of SorA will go beyond HIV and HCV, which is something that the laboratories of Dr. Diez and Dr. Meyerhans are already testing. The concept of broad-spectrum antivirals targeting host cells and obtained from nature as well as the characteristics of the inhibition of HCV mediated by SorA are published in two articles. It is still very early to speak of SorA in treatment. From an antiviral compound being effective in cell cultures to it coming to be used on patients is very long process. But the experimental discoveries so far are very promising. The development of medicine with broad-spectrum antiviral activities may be a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of the many viruses, yet the event of such host-targeting drugs has been met with scepticism mainly thanks to toxicity issues and poor translation to in vivo models. With the arrival of latest and more powerful screening assays and prediction tools, the thought of a drug which will efficiently treat a good range of viral infections by blocking specific host functions has re-bloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral discovery. We discuss putative targets and treatment strategies, with particular specialise in natural products as promising starting points for antiviral lead development. Viral infections affect millions of people every year and are a global public health threat. Infections with viruses like HIV or HCV can become persistent and may produce severe diseases as AIDS or hepatocellular carcinoma, respectively. (Re-)emerging viruses like WNV, DENV or CHIKV are spreading without proper control mechanisms. Thus, there are no effective vaccines and the treatment options against most virus threads are still limited. In this context, the development of new antivirals remains an important issue. Viruses need cellular host factors to complete their life cycles. Hundreds of these host-factors have been identified. Interestingly, several viruses use the same host factors so that chemical inhibition of these may lead to broad-spectrum viral inhibition. Broad-spectrum host-acting antivirals (HAAs) may increase the barrier to resistance development and reduce the complexity of co-infection treatments. In this thesis a high-throughput anti-HIV screening was applied to a myxobacteria metabolites library. Compounds with high anti-HIV activity and low toxicity were identified as hits and 2 of them (ratjadone A and soraphen A) were selected for further research. Ratjadone A inhibits the CRM1-mediated nuclear export and soraphen A inhibits the de novo fatty acid synthesis. Both drugs inhibit HIV and we described the mechanisms of inhibition of both compounds. The data presented in this thesis suggest that the use of host-acting antivirals as a broad-spectrum therapy is a feasible option.

Development of anti-HIV peptides based on a viral capsid protein.

Peptide inhibitors with cell permeability targeting an HIV-1 capsid (CA) protein might make therapeutic by regulating HIV-1 replication. Overlapping fragment peptide libraries covering the whole sequence of an HIV-1 CA protein have been synthesized with the addition of an octa-arginyl moiety to increase their cell permeability. Amongst these peptides, several compounds which inhibit the HIV-1 replication cycle have been found. Conjugation of cell-penetrating functions such as an octa-arginyl group to individual peptides in combination with the addition of chloroquine in cell-based anti-HIV assays was previously proven to be a useful assay method with which to search for active peptides. Anti-HIV assays have been performed in the presence or absence of chloroquine and found that most of compounds have higher anti-HIV activity in the presence, rather than in the absence of chloroquine. Some potent seeds as anti-HIV agents might naturally lie hidden in CA proteins, and could become useful leads to HIV inhibitors.

Antiviral and Antitumor Activity of Licorice Root Extracts.

In the search for anti-viral and antitumor substances from natural resources, antiviral and antitumor activities of licorice root extract and purified ingredients were investigated. Viability of cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Antiviral activity was quantified by the selectivity index, defined as the ratio of the 50% cytotoxic concentration (CC50) to the 50% effective concentration against human immunodeficiency virus (HIV) or herpes simplex virus (HSV)-infected cells (EC50). The tumor specificity was calculated by the ratio of CC50 against human normal oral cells to that against human oral squamous cell carcinoma cell lines. Licorice flavonoids and lower molecular polyphenols were subjected to quantitative structure-activity relationship analysis. Alkaline extract of licorice root had higher anti-HIV activity than did water extracts, confirming our previous reports. On the other hand, water extract, especially the flavonoid-rich fraction, had higher anti-HSV activity than did the alkaline extract. The flavonoid-rich fraction was more cytotoxic against human oral squamous cell carcinoma cell lines compared to normal oral cells, suggesting their tumor-specific cytotoxicity. The present study suggests that water and alkaline extracts of licorice root exert different mechanisms of actions against these two viruses. Physicochemical properties, rather than the category of compounds, may be important in determining their anti-HSV activity.

Synthesis and antiviral properties of new derivatives of 2-(alkylsulfanyl)-6-[1-(2,6-difluorophenyl)cyclopropyl]-5-methylpyrimidin-4(3H)-one

Based on 2-(2,6-difluorophenyl)acetonitrile a synthesis was performed of new bioisosteric prochiral analogs of anti-HIV-1 active derivatives of 2-alkoxy-6-benzylpyrimidin-4(3Н)-one that we had previously obtained. The study using infected and nonifected strains of cells MT-4 made it possible to find in all prepared compounds a high anti-HIV activity whereas the cytotoxicity of the substances depended strongly on the structure of the alkylsulfanyl fragment of the molecule.

Chemically sulfated natural galactomannans with specific antiviral and anticoagulant activities

Naturally occurring galactomannans were sulfated to give sulfated galactomannans with degrees of substitution of 0.7–1.4 per sugar unit and molecular weights of M¯n=0.6×104–2.4×104. Sulfated galactomannans were found to have specific biological activities in vitro such as anticoagulant, anti-HIV and anti-Dengue virus activities. The biological activities were compared with those of standard dextran and curdlan sulfates, which are polysaccharides with potent antiviral activity and low cytotoxicity. It was found that sulfated galactomannans had moderate to high anticoagulant activity, 13.4–36.6unit/mg, compared to that of dextran and curdlan sulfates, 22.7 and 10.0unit/mg, and high anti-HIV and anti-Dengue virus activities, 0.04–0.8μg/mL and 0.2–1.1μg/mL, compared to those curdlan sulfates, 0.1μg/mL, respectively. The cytotoxicity on MT-4 and LCC-MK2 cells was low. Surface plasmon resonance (SPR) of sulfated galactomannans revealed strong interaction with poly-l-lysine as a model compound of virus proteins, and suggested that the specific biological activities might originate in the electrostatic interaction of negatively charged sulfate groups of sulfated galactomannans and positively charged amino groups of surface proteins of viruses. These results suggest that sulfated galactomannans effectively prevented the infection of cells by viruses and the degree of substitution and molecular weights played important roles in the biological activities.

SYNTHESIS OF METAL-ORGANIC (COMPLEXES) COMPOUNDS COPPER(II)-IMIDAZOLE FOR ANTIVIRAL HIV CANDIDATE

The human immunodeficiency virus (HIV) is viruses known as rotaviruses. Potential target for therapeutic is reverse transcriptase (RT), possesses an RNA-dependent DNA polymerase, DNA-dependent DNA polymerase and ribonuclease H fuctions. Imidazoles have high anti-HIV inhibitory activity, some derivates of imidazole reported drugs. 8-chloro-2,3-dihydroimidazole[1,2-b][1,4,2]benzodithiazine-5,5-dioxides and 9-chloro-2,3,4-trihydropyri-mido[1,2-b][1,4,2]benzodithi-azine-6,6-dioxides. This compounds succesfully identified anti-HIV activity. Copper is a bio-essential element and copper complexes have been extensively utilized in metal mediated DNA cleavage for the generation of activated oxygen species. It has been reported that teraaza macrocyclic copper coordination compounds have anti-HIV activities. Studies have shown that these macrocyclic complexes can react with DNA in different binding fashions and exhibit effective nuclease activities. Complex compounds are compounds in which there is an atom that acts as the central atom and trotter group of molecules that can be either neutral or charged ions. Application a metal-organic (complex) compounds, especially copper metal and derivates of imidazole. So, in this study can explore new anti-HIV candidate.

A minimally cytotoxic CD4 mimic as an HIV entry inhibitor.

Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.

The Effect of Gendarussin a Isolates of Justicia gendarussa Burm.f. Leaf in Reverse Transcriptase Inhibition of HIV Type I In Vitro

Screening has been done to a few extracts from the leaves Justicia gendarussa Burm.f to see the growth rate of the virus from the blood plasma of HIV patients at Dr Soetomo Hospital. It is known that J. gendarussa leaf extract inhibits HIV type 1 reverse transcriptase. In addition, its main content is gendarussin A, besides gendarussin B, JGF1, JGF2 and JGF3, which have just identified. At the beginning, extraction and fractionation were performed with 3 models that highlight the absolute methanol, 70% methanol and 70% ethanol with the release of alkaloids. Furthermore, samples of each fraction were incubated in plasma of HIV patients with a titer of 3.6 10^6 copies for 1 h in concentrations of 1.64 ppm, 4.1 ppm, 8.2 ppm, 16.4 ppm and 41.0 ppm. After incubation, examination was performed by using Nucli sens a machine, which is a combination of PCR and Elisa, thus avoiding direct contact with the highly pathogenic virus. The result showed that the activity sequence from the most potential to the weak, among others, was 1.64 ppm >4.1 ppm > 8.2 ppm > 16.4 ppm > 41.0 ppm, each with barriers value of 0.62 10^6, 1.4 10^6, 1.6 10^6, 2.4 10 cells/ml. In conclusion, highest anti-HIV activity comes from the concentration of gendarussin A isolate at 1.64 ppm. Furthermore, after linear regression of y = -3.063 x + 81.37 was done, the IC50 of 10.24 ppm was obtained.

New hybrids between triterpenoid acids and nucleoside HIV-RT inhibitors

One-pot synthesis of ester-linked conjugates of betulinic, ursolic or oleanolic acids with anti-HIV drugs AZT, derivatives of AZT and 3TC was performed, the resulting conjugates having shown high anti-HIV activities.

Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors.

Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity.

Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10 nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.