Ursane and 24-Noroleanane-Type Triterpenoids with Anti-HIV Activity from the Twigs and Leaves of Antirhea chinensis.

Investigations on the twigs and leaves of Antirhea chinensis have led to the discovery of two undescribed pentacyclic triterpenoids (1 and 2) and nine known analogs. Compounds 1 and 2, each assigned as the ursane and 24-noroleanane-type triterpenoids, featuring similar oxidation pattern of 3ß,6ß,19α-trihydroxy-28-carboxyl. Their structures were elucidated via comprehensive analyses of spectroscopic data. Compound 1 displayed potent anti-HIV activity (EC50 =1.24 µM) and high selectivity index (SI >32.3).

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold-A Short Review of Most Recent Studies 2013-2022.

The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013-2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure-Activity-Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.

Anti-HIV Ermiasolides from Croton megalocarpus.

In recent years, elucidation of novel anti-HIV bioactive compounds from natural products is gaining importance rapidly, not only from the research and publications, but also from controlled clinical studies. Here we report three new anti-HIV eudesmane-type sesquiterpenes, 5ß-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), 5ß,8α-Dihydroxy eudesm-7(11)-en-12,8-olide (2) and 5ß-Hydroxy-8H-ß-eudesm-7(11)-en-12,8-olide (3). These are trivially named ermiasolide A-C and were isolated from the bark of Croton megalocarpus. 5ß-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), showed the highest anti-HIV activity by inhibiting 93% of the viral replication with an IC50 = 0.002 µg/mL. On the other hand, 5ß-Hydroxy-8H-ß-eudesm-7(11)-en-12,8-olide (3) and 5ß,8α-dihydroxy eudesm-7(11)-en-12,8-olide (2), inhibited viral replication by 77.5% at IC50 = 0.04 µg/mL and 69.5% at IC50 = 0.002 µg/mL, respectively. Molecular docking studies showed that the proposed mechanism of action leading to these results is through the inhibition of HIV-protease.

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir.

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97-99% inhibition) at 10-100 ng/mL but was more potent than TAF when compared at molar concentration.

New phorbol ester derivatives as potent anti-HIV agents.

Tigliane esters show many biological activities, including anti-HIV-1 activity. Our aim in this study was to establish structure-anti-HIV activity relationships for four series of tigliane-type diterpenoids. We synthesized and evaluated 29 new phorbol ester derivatives for anti-HIV activity and for cytotoxicity against human tumor cell lines. Among them, three derivatives, two phorbol-13-monoesters (5d and 5e) and a phorbol-12,13-diester (6a), showed significant anti-HIV activity. We found that better anti-HIV activity was often associated with a shorter acyl ester at C-13. Particularly, compounds with a phenyl ring in the ester side chain exhibited excellent anti-HIV activity and had good safety indexes. Due to its significant anti-HIV potency with a high selectivity index, phorbol-12,13-dicinnamoate (6a) was chosen as the potential candidate for further preclinical trials.

Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M.

One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-ß (TGF-ß). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.

Comparative biological study between quinazolinyl-triazinyl semicarbazide and thiosemicarbazide hybrid derivatives.

Practical synthesis and biological activities of quinazolinyl-triazinyl semicarbazides (10a-j) and quinazolinyl-triazinyl thiosemicarbazides (11a-j) have been described. The novel semicarbazides and thiosemicarbazides were prepared by condensation of different nucleophiles like isocyanate and isothiocyanate by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized quinazolinyl-triazinyl semicarbazide and thiosemicarbazide derivatives were evaluated for their expected antimicrobial activity. All the final synthesized derivatives were characterized by their melting point, mass spectra, 1H NMR and 13C NMR as well as elemental microanalysis. The final analogues were then analyzed for their in vitro antimicrobial activity against bacteria (Gram positive and negative) and fungus using the agar streak dilution method as well as in vitro anti-HIV activity against two types of viral strains, viz. HIV type I (IIIB) and type II (ROD) by using MTT assay method. SAR and HOMO-LUMO studies were also carried out for proving the structural biological activity. Among them, compounds 10e, 10f, 11h and 11j gave best results as their energy gap is very low which makes their activity higher.

Recent advances in natural anti-HIV triterpenoids and analogs.

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses the anti-HIV triterpenoids and analogs reported during the period of 2009-2019. The article includes not only a comprehensive review of the recent anti-HIV agent development from the perspective of medicinal chemistry, but also discusses structure-activity relationship analyses of the described triterpenoids.

Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7.

In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 µM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 µM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.

Role of medicinal plants in HIV/AIDS therapy.

Human immunodeficiency virus (HIV) causes the potentially life-threatening and chronic disease called acquired immune deficiency syndrome (AIDS). The main target of this viral disease is to suppress the immune system and make the body unresponsive to external stimuli. According to global health observatory data since epidemic, more than 78 million people were affected by HIV and 39 million people died globally. Until 2017, 36.5 million people were living with HIV. An estimated 0.8% (0.6%-0.9%) of adults aged 15-49 years worldwide is living with HIV. The World Health Organization (WHO) reported that the African region remains most severely affected, with nearly one in every 25 adults (4.1%) living with HIV and accounting for nearly two-thirds of the people living with HIV worldwide. WHO reported that globally only 21.7 million (19.1 million-22.6 million) people have had access to antiretroviral therapy up to 2017. Currently, antiretroviral therapy (ART) is available for the control of HIV but has serious associated side effects such as lipodystrophy. Because of the limitations, associated with ART, researchers throughout the world are trying to explore and develop more reliable and safe drugs from natural resources to manage HIV infection. A wide range of medicinal plants have been studied and have reported significant potential against HIV. Plants like Rheum palmatum L., Rheum officinale, Trigonostem axyphophylloides, Vatica astrotricha, Vernonia amygdalina, Hypoxias pelargonium, Sidoides hemerocallidea and Sutherlandia frutescens etc. have high efficacy to cure HIV. The exact mechanism of action is still not known but various phytoconstituents isolated from medicinal plants such as alkaloids, flavonoids, polyphenols, terpenoids, tannins, proteins and coumarins have the potential to interrupt the life cycle of HIV as well as act as immunomodulators to enhance the immune system of infected patients with no well reported side effects. It could be concluded that medicinal plants have potential for the management of HIV/AIDS but more studies are needed to reveal rigorous efficacy and safety concerns by conducting clinical trials at vast level to explore therapeutic impact of medicinal plants.

Cordidepsine is A Potential New Anti-HIV Depsidone from Cordia millenii, Baker.

Chemical investigation of Cordia millenii, Baker resulted in the isolation of a new depsidone, cordidepsine (1), along with twelve known compounds including cyclooctasulfur (2), lup-20(29)-en-3-triacontanoate (3), 1-(26-hydroxyhexacosanoyl)glycerol (4), glyceryl-1-hexacosanoate (5) betulinic acid (6), lupenone (7), ß-amyrone (8), lupeol (9), ß-amyrin (10), allantoin (11), 2'-(4-hydroxyphenyl)ethylpropanoate (12) and stigmasterol glycoside (13). Hemi-synthetic reactions were carried out on two isolated compounds (5 and 6) to afford two new derivatives, that is, cordicerol A (14) and cordicerol B (15), respectively. The chemical structures of all the compounds were established based on analysis and interpretation of spectroscopic data such as electron ionization mass spectrometry (EI-MS), high resolution electrospray ionization mass spectrometry (HR-ESI-MS), fast atom bombardment mass spectrometry (FAB-MS), one dimension and two dimension nuclear magnetic resonance (1D and 2D-NMR) spectral data as well as X-ray crystallography (XRC). Lupeol ester derivatives [Lup-20(29)-en-3-triacontanoate (3)], monoglycerol derivatives [1-(26-hydroxyhexacosanoyl)glycerol (4) and glyceryl-1 hexacosanoate (5)] were isolated for the first time from Cordia genus while sulfur allotrope [cyclooctasulfur (2)] was isolated for the first time from plant origin. Biological assays cordidepsine (1) exhibited significant anti-HIV integrase activity with IC50 = 4.65 µM; EtOAc extract of stem barks, EtOAc fraction of roots and leaves were not toxic against 3T3 cells.

First discovery of a potential carbonate prodrug of NNRTI drug candidate RDEA427 with submicromolar inhibitory activity against HIV-1 K103N/Y181C double mutant strain.

In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50 = 0.264 µM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug.

Isolation and structure determination of a new lasso peptide specialicin based on genome mining.

Based on genome mining, a new lasso peptide specialicin was isolated from the extract of Streptomyces specialis. The structure of specialicin was established by ESI-MS and NMR analyses to be a lasso peptide with the length of 21 amino acids, containing an isopeptide bond and two disulfide bonds in the molecule. The stereochemistries of the constituent amino acids except for Trp were determined to be L and the stereochemistry of Trp at C-terminus was determined to be D. Three dimensional structure of specialicin was determined based on NOE experimental data, which indicated that specialicin possessed the similar conformational structure with siamycin I. Specialicin showed the antibacterial activity against Micrococcus luteus and the moderate anti-HIV activity against HIV-1 NL4-3. The biosynthetic gene cluster of specialicin was proposed from the genome sequence data of S. specialis.

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity.

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 µM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 µM and could be a promising antiproliferative agent.

Synthesis and Antiviral Activity of Water-Soluble Polycarboxylic Derivatives of [60]Fullerene Loaded with 3,4-Dichlorophenyl Units.

We have synthesized a series of water-soluble polycarboxylic derivatives of [60]fullerene with a gradually changed polarity by combining three to five polar (ionic) malonate addends with two to zero hydrophobic dichlorobenzene units and explored their antiviral activity. It has been shown that decreasing the number of the ionogenic carboxylic groups in the molecules enhanced their antiviral activity against HIV-1 and suppressed their action against HIV-2. The obtained results implied that the charged states and hydrophobicity of the water-soluble polycarboxylic fullerene derivatives affect significantly their biological properties.

Salicylic acid derivatives and phenylspirodrimanes from the sponge-associated fungus Hansfordia sinuosae.

Three new salicylic acid derivatives (1-3) and a known one, 6-(3'-hydroxypropyl)-2-hydroxybenzoic acid (4), together with seven known phenylspirodrimanes (5-11), were isolated from the sponge-associated fungus Hansfordia sinuosae, collected from the South China Sea. HRESIMS, FT-IR Spectroscopy, and NMR techniques including COSY, HSQC, and HMBC were used to elucidate the structures of these compounds. The inhibitory effects of the isolated compounds (1-11) against HIV-1 virus were evaluated, and most of the phenylspirodrimanes (5, 8-11) showed varying degrees of anti-HIV activity.

Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas.

A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.

Bioactive steroids and sorbicillinoids isolated from the endophytic fungus Trichoderma sp. Xy24.

A new steroid glucoside (1), along with nine known steroids (2-10) and four known sorbicillinoids (11-14), were isolated from the endophytic fungus Trichoderma sp. Xy24. Their structures were elucidated on the basis of spectroscopic data analyses and by comparison with reported data. Compounds 3, 5-7, 9, 10, and 13 exhibited significant inhibitory effects on HIV-1 virus with IC50 values ranging 1.9-9.3 µM; compounds 10, 13, and 14 showed potent inhibitory activity on LPS-induced NO production in BV2 microglia cells with inhibitory rates of 108.2, 100, and 75.1% at 10 µM, respectively. In addition, compound 10 displayed moderate cytotoxicity against BCG823 and HePG2 cell lines with IC50 values of 11.1 and 17.7 µM, respectively.

Neoflavonoids as Inhibitors of HIV-1 Replication by Targeting the Tat and NF-κB Pathways.

Twenty-eight neoflavonoids have been prepared and evaluated in vitro against HIV-1. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase reporter gene. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Seven 4-phenylchromen-2-one derivatives showed HIV transcriptional inhibitory activity but only the phenylchrome-2-one 10 inhibited NF-κB and displayed anti-Tat activity simultaneously. Compounds 10, 14, and 25, inhibited HIV replication in both targets at concentrations <25 µM. The assays of these synthetic 4-phenylchromen-2-ones may aid in the investigation of some aspects of the anti-HIV activity of such compounds and could serve as a scaffold for designing better anti-HIV compounds, which may lead to a potential anti-HIV therapeutic drug.

Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity.

Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.