Plant Coumarins with Anti-HIV Activity: Isolation and Mechanisms of Action

This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.


Introduction
Coumarin is a heterocyclic system of annulated pyrone and benzene rings. Coumarins are widely distributed in the plant kingdom, and are present in the roots, stems, bark, leaves, seeds, fruits, or flowers of various plant species. While unsubstituted coumarin can have significant hepatotoxicity [1], oxygenated coumarin derivatives generally have low toxicity [2] (expect aflatoxin coumarins), which may be due to the destructive opening of the pyrone ring [3] and hydroxylation [2] leading to the formation of easily excreted highly hydrophilic products. These properties offer great potential for combining coumarin derivatives with other compounds in the treatment of diseases [4,5]. This is especially important for the highly effective antiretroviral therapy proposed by David Ho in 1996 [6,7].
In addition, the synthesis of hydroxyl-containing coumarins by Pechmann condensation [8,9] is a convenient protocol, which makes this class of heterocyclic compounds particularly easy to access, both in terms of obtaining libraries of compounds to optimize the structure of the drug lead and in terms of large-scale industrial production.
Over the past 30 years, natural coumarin compounds have attracted great attention as lead compounds for developing low molecular weight antiviral agents, particularly anti-HIV agents [10,11]. Despite the fact that there are no approved coumarin derivatives in clinical practice, several natural and semi-synthetic coumarins have recently been discovered and are currently undergoing various phases of clinical trials [12].
The HIV replication cycle consists of thirteen steps (Figure 1) [13]; each step can be the target of chemotherapeutic interventions. The viral cycle begins with virion attachment to the membrane receptor of the T cell (step 1), followed by entry of viral components into the cell (step 2). Uncoated viral reverse transcriptase (RT) and viral RNA trigger reverse transcription (step 4), producing viral DNA, which is transported to the nucleus (step 5) and incorporated into the DNA of the infected cell (step 6). Viral RNA is synthesized in the nucleus (step 7), and the viral RNA leaves the nucleus (step 8) and serves to synthesize Currently, the vast majority of antiretroviral drugs target the steps of reverse transcription and integration (steps 4 and 6). In 2022, there were 14 FDA-approved reverse transcriptase and integrase inhibitors, while only 7 drugs that aimed to block the remaining 11 stages had been approved [14]. RT inhibitors can be nucleoside or non-nucleoside RT inhibitors (NRTIs and NNRTIs). NRTIs contain a nucleoside base, which is incorporated into the growing DNA chain, terminating its elongation, while NNRTIs block the active site of the RT itself.
In terms of the mechanism of antiviral action, anti-HIV coumarins can be divided into four groups ( Figure 2): NNRTIs (this group includes simple coumarins I, linear furocoumarins IIa, as well as both angular and linear pyranocoumarins IIIa and IIIb, respectively), the largest group; integrase inhibitors (coumestans IIb); compounds inhibiting cellular factors that regulate HIV-1 replication, for example, by inhibition of the transcription factor NF-κB (simple coumarins I, pyranocoumarins IIIc); and inhibitors of the transmission of viral particles from infected macrophages to healthy ones, for example, inhibiting HIV-1 Currently, the vast majority of antiretroviral drugs target the steps of reverse transcription and integration (steps 4 and 6). In 2022, there were 14 FDA-approved reverse transcriptase and integrase inhibitors, while only 7 drugs that aimed to block the remaining 11 stages had been approved [14]. RT inhibitors can be nucleoside or non-nucleoside RT inhibitors (NRTIs and NNRTIs). NRTIs contain a nucleoside base, which is incorporated into the growing DNA chain, terminating its elongation, while NNRTIs block the active site of the RT itself.
In terms of the mechanism of antiviral action, anti-HIV coumarins can be divided into four groups ( Figure 2): NNRTIs (this group includes simple coumarins I, linear furocoumarins IIa, as well as both angular and linear pyranocoumarins IIIa and IIIb, respectively), the largest group; integrase inhibitors (coumestans IIb); compounds inhibiting cellular factors that regulate HIV-1 replication, for example, by inhibition of the transcription factor NF-κB (simple coumarins I, pyranocoumarins IIIc); and inhibitors of the transmission of viral particles from infected macrophages to healthy ones, for example, inhibiting HIV-1 entry, and downregulating the expression of chemokine receptors CXCR4, CD4, and CCR5 (simple coumarins I, furocoumarins IIa, and pyranocoumarins IIIa). In addition, for some compounds there are still no reliable data on the mechanism of action [15]. Therefore, typical coumarins with anti-HIV activity are RT and integrase inhibitors, so they can potentially be used as components of highly effective antiretroviral therapy. entry, and downregulating the expression of chemokine receptors CXCR4, CD4, and CCR5 (simple coumarins I, furocoumarins IIa, and pyranocoumarins IIIa). In addition, for some compounds there are still no reliable data on the mechanism of action [15]. Therefore, typical coumarins with anti-HIV activity are RT and integrase inhibitors, so they can potentially be used as components of highly effective antiretroviral therapy. Naturally occurring anti-HIV coumarins may be classified by their structure into three main groups: simple coumarins I, furocoumarins (psoralene-type IIa and coumestan-type IIb), and pyranocoumarins (angular IIIa and linear IIIb) ( Figure 2) [16].
This review provides a full account of simple coumarins I and their annulated analogs II and III as potential anti-HIV agents, with emphasis on recent articles published in the last 5 years. Since not all coumarins have a known mechanism of anti-HIV action but all have a known structure, in this review, we have systematized the antiviral coumarins according to their structure.

Simple Coumarins
In the group of simple coumarins, we included compounds that contain the benzopyrone system and do not contain other cycles annulated with it; substituted coumarins are also included in this section. Simple natural coumarins usually contain methoxy, hydroxy groups and/or 1-3 prenyl residues as substituents of benzo or pyran rings via an optional -O-linker.
This review provides a full account of simple coumarins I and their annulated analogs II and III as potential anti-HIV agents, with emphasis on recent articles published in the last 5 years. Since not all coumarins have a known mechanism of anti-HIV action but all have a known structure, in this review, we have systematized the antiviral coumarins according to their structure.

Simple Coumarins
In the group of simple coumarins, we included compounds that contain the benzopyrone system and do not contain other cycles annulated with it; substituted coumarins are also included in this section. Simple natural coumarins usually contain methoxy, hydroxy groups and/or 1-3 prenyl residues as substituents of benzo or pyran rings via an optional -O-linker.
Farnesiferol C 8 (Table 1) is a well-known sesquiterpene coumarin isolated from genus Ferula (Apiaceae) species such as Ferula assafoetida and Ferula szowitsiana. It has been reported to have cytotoxic, apoptotic, MDR reversal, antitumor, antimutagenic, and antiviral activity [34]. Recently, farnesiferol C 8 was identified as an HIV-1 RT inhibitor with a mixed inhibition mechanism (IC50 = 30 μM). Using theoretical and experimental methods, it was demonstrated that farnesiferol C 8 could quench the intrinsic fluorescence emission of HIV-1 RT through a static quenching mechanism, while molecular docking studies indicated that farnesiferol C 8 interacts with the enzyme through a hydrophobic pocket [35].
Farnesiferol C 8 (Table 1) is a well-known sesquiterpene coumarin isolated from genus Ferula (Apiaceae) species such as Ferula assafoetida and Ferula szowitsiana. It has been reported to have cytotoxic, apoptotic, MDR reversal, antitumor, antimutagenic, and antiviral activity [34]. Recently, farnesiferol C 8 was identified as an HIV-1 RT inhibitor with a mixed inhibition mechanism (IC50 = 30 μM). Using theoretical and experimental methods, it was demonstrated that farnesiferol C 8 could quench the intrinsic fluorescence emission of HIV-1 RT through a static quenching mechanism, while molecular docking studies indicated that farnesiferol C 8 interacts with the enzyme through a hydrophobic pocket [35].
Farnesiferol C 8 (Table 1) is a well-known sesquiterpene coumarin isolated from genus Ferula (Apiaceae) species such as Ferula assafoetida and Ferula szowitsiana. It has been reported to have cytotoxic, apoptotic, MDR reversal, antitumor, antimutagenic, and antiviral activity [34]. Recently, farnesiferol C 8 was identified as an HIV-1 RT inhibitor with a mixed inhibition mechanism (IC50 = 30 μM). Using theoretical and experimental methods, it was demonstrated that farnesiferol C 8 could quench the intrinsic fluorescence emission of HIV-1 RT through a static quenching mechanism, while molecular docking studies indicated that farnesiferol C 8 interacts with the enzyme through a hydrophobic pocket [35].
Farnesiferol C 8 (Table 1) is a well-known sesquiterpene coumarin isolated from genus Ferula (Apiaceae) species such as Ferula assafoetida and Ferula szowitsiana. It has been reported to have cytotoxic, apoptotic, MDR reversal, antitumor, antimutagenic, and antiviral activity [34]. Recently, farnesiferol C 8 was identified as an HIV-1 RT inhibitor with a mixed inhibition mechanism (IC50 = 30 μM). Using theoretical and experimental methods, it was demonstrated that farnesiferol C 8 could quench the intrinsic fluorescence emission of HIV-1 RT through a static quenching mechanism, while molecular docking studies indicated that farnesiferol C 8 interacts with the enzyme through a hydrophobic pocket [35].
Diterpene derivatives represent a large class of terpene coumarins, which usually have the highest anti-HIV activity. The low toxicity of coumarin O-terpenoids (up to 813 μM) allows for an acceptable TI in spite of the low EC50 (5 to 60 μM).
C-terpenoid anti-HIV coumarin derivatives are represented by a large number of compounds. In general, C-terpenoids are characterized by higher activity compared to their O-counterparts. Among them, it is possible to distinguish monoterpenoids and diterpenoids (Table 2).
T. Okuda and colleagues demonstrated that 3-arylcoumarin, namely glycycoumarin 30 (Figure 4), isolated from licorice inhibits giant cell formation in HIV-infected cultures at 20 μg/mL without any observed cytotoxicity [32]. Later, J. Alcami et al. studied natural 4-phenyl-coumarins isolated from the Marila pluricostata plant (family Clusiaceae) for their activity against HIV transcription, which occurred by the mechanism of inhibition of the transcription factor NF-κB and by the function of transactivation of transcription (Tat). Among the studied coumarins, only two derivatives (disparinol A 31 and isodispar B 32 ( Figure 4)) showed high inhibitory efficacy towards NF-κB proteins (81.0% and 55.4% at 25 μM respectively) and Tat (similar for both, ~40% at 25 μM and ~70% at 50 μM) [54]. Bichromonol demonstrated micromolar activity with EC50 = 6.6-12.0 μM against both wild-type HIV-1 and its clinically relevant mutant strains. Bichromonol is particularly more effective than the commercial drug nevirapine against the resistant variants A17 and EFVR, and might thus have the potential to serve as a new anti-HIV lead. Unfortunately, there are still no reliable data on the mechanism of anti-HIV action of bichromonol. Since simple coumarins typically inhibit HIV RT, it was suggested that bichromonol is an HIV RT inhibitor. However, preliminarily enzymatic assay reveals no RT inhibitory activity of compound 33. For the anti-HIV activity of simple coumarins, the key factor is the presence of certain substituents. Since all simple coumarins inhibit HIV RT, a structure-activity relationship T. Okuda and colleagues demonstrated that 3-arylcoumarin, namely glycycoumarin 30 (Figure 4), isolated from licorice inhibits giant cell formation in HIV-infected cultures at 20 µg/mL without any observed cytotoxicity [32]. Later, J. Alcami et al. studied natural 4-phenyl-coumarins isolated from the Marila pluricostata plant (family Clusiaceae) for their activity against HIV transcription, which occurred by the mechanism of inhibition of the transcription factor NF-κB and by the function of transactivation of transcription (Tat). Among the studied coumarins, only two derivatives (disparinol A 31 and isodispar B 32 (Figure 4)) showed high inhibitory efficacy towards NF-κB proteins (81.0% and 55.4% at 25 µM respectively) and Tat (similar for both,~40% at 25 µM and~70% at 50 µM) [54].
In 2022, Fobofou et al. reported a new type of coumarin dimer with activity against HIV [15]. In particular, 8,8'-dicoumarin derivative (bichromonol) 33 ( Figure 5) isolated from the stem bark of Hypericum roeperianum exhibits anti-HIV activity in infected MT-4 cells. Bichromonol demonstrated micromolar activity with EC 50 = 6.6-12.0 µM against both wild-type HIV-1 and its clinically relevant mutant strains. Bichromonol is particularly more effective than the commercial drug nevirapine against the resistant variants A17 and EFVR, and might thus have the potential to serve as a new anti-HIV lead. Unfortunately, there are still no reliable data on the mechanism of anti-HIV action of bichromonol. Since simple coumarins typically inhibit HIV RT, it was suggested that bichromonol is an HIV RT inhibitor. However, preliminarily enzymatic assay reveals no RT inhibitory activity of compound 33.
A17 and EFVR, and might thus have the potential to serve as a new anti-H tunately, there are still no reliable data on the mechanism of anti-HIV ac monol. Since simple coumarins typically inhibit HIV RT, it was suggest monol is an HIV RT inhibitor. However, preliminarily enzymatic assay re hibitory activity of compound 33. For the anti-HIV activity of simple coumarins, the key factor is the pres substituents. Since all simple coumarins inhibit HIV RT, a structure-activi For the anti-HIV activity of simple coumarins, the key factor is the presence of certain substituents. Since all simple coumarins inhibit HIV RT, a structure-activity relationship seems possible for them. Coumarins with only hydroxy or methoxy groups (compounds 1-3) tend to have low anti-HIV activity; O-terpenoid and C-monoterpenoid coumarins 5-8 and 9-18 often have acceptable characteristics, while diterpenes 19-28 mostly have high activity (EC 50 reaches the nanomolar range). The most active diterpene coumarins contain isoprene substituents at the C3 and C6 positions.
In addition, simple diterpene coumarins have a low molecular weight, and their activity is tolerant to the introduction of polar substituents (compounds 22-27). Therefore, in our opinion, diterpene coumarins are promising lead compounds for developing new anti-HIV agents. In development, attention should probably be paid to unsaturated double bonds, which pose a potential problem in terms of drug stability and drug metabolism.

Furocoumarins
Furocoumarins are a class of compounds of natural and synthetic origin with various biological activities. Among natural furocoumarins, two classes of anti-HIV agents are distinguished: psoralene-type IIa and coumestan-type IIb ( Figure 6). Due to the plane structure of psoralene, it intercalates into the DNA helix, forming strong bonds with nitrogenous bases [55]. This property is used in the photochemical treatment of skin diseases [55][56][57]. In addition, simple diterpene coumarins have a low molecular weigh tivity is tolerant to the introduction of polar substituents (compounds 22in our opinion, diterpene coumarins are promising lead compounds for d anti-HIV agents. In development, attention should probably be paid to un ble bonds, which pose a potential problem in terms of drug stability and dru

Furocoumarins
Furocoumarins are a class of compounds of natural and synthetic orig biological activities. Among natural furocoumarins, two classes of anti-H distinguished: psoralene-type IIa and coumestan-type IIb ( Figure 6). Du structure of psoralene, it intercalates into the DNA helix, forming strong trogenous bases [55]. This property is used in the photochemical treatment [55][56][57]. It was demonstrated that furocoumarins 34-43 inhibit HIV replicat with an EC50 in the range of up to 0.37 μM (Table 3) [30,58]. Among them, are psoralen 33 (EC50 = 0.54 and TI = 191), bergapten 35 (EC50 = 1.63 and T torin 36 (EC50 < 0.37 and TI > 1000) and heraclenol 40 (EC50 = 0.38 and TI Subsequently, Sancho and colleagues showed that imperatorin 36 show against RT and integrase [59]. However, it inhibits the critical transcription blocks infected cells in the G1 phase of the cell cycle. This indicates its pote tic role in the treatment of HIV infections by inhibiting cellular factors tha 1 replication at the transcriptional level [59]. Table 3. Linear furocoumarins with anti-HIV activity.  [30,58]. Subsequently, Sancho and colleagues showed that imperatorin 36 showed no activity against RT and integrase [59]. However, it inhibits the critical transcription factor Sp1 and blocks infected cells in the G1 phase of the cell cycle. This indicates its potential therapeutic role in the treatment of HIV infections by inhibiting cellular factors that regulate HIV-1 replication at the transcriptional level [59]. Table 3. Linear furocoumarins with anti-HIV activity.

Compound
Plant Source Anti-HIV Activity and Toxicity torin 36 (EC50 < 0.37 and TI > 1000) and heraclenol 40 (EC50 = 0.38 and TI = 870) [3 Subsequently, Sancho and colleagues showed that imperatorin 36 showed no ac against RT and integrase [59]. However, it inhibits the critical transcription factor Sp blocks infected cells in the G1 phase of the cell cycle. This indicates its potential ther tic role in the treatment of HIV infections by inhibiting cellular factors that regulate 1 replication at the transcriptional level [59]. Table 3. Linear furocoumarins with anti-HIV activity.

Compound Plant Source Anti-HIV Activity a Toxicity
Psoralen 34 Prangos tschimganica [58], Ruta graveolens [60], torin 36 (EC50 < 0.37 and TI > 1000) and heraclenol 40 (EC50 = 0.38 and TI = 870) [3 Subsequently, Sancho and colleagues showed that imperatorin 36 showed no act against RT and integrase [59]. However, it inhibits the critical transcription factor Sp1 blocks infected cells in the G1 phase of the cell cycle. This indicates its potential thera tic role in the treatment of HIV infections by inhibiting cellular factors that regulate 1 replication at the transcriptional level [59]. Table 3. Linear furocoumarins with anti-HIV activity.
Wedelolactone 46 (Figure 8) isolated from Eclipta prostrate plants also demonstrated selective inhibition of HIV-1 integrase with IC50 = 4 μM [71]. It should be noted that wedelolactone is the only coumarin that has activity against HIV integrase. In addition, wedelolactone has weak protease inhibition activity (32.7% at 100 μM) [71].  The second group of natural furocoumarins is the coumestans. They are mainly distributed in plants of the Fabaceae family [26,[66][67][68][69] and have a wide spectrum of biological activity [70]. However, the antiviral activity of coumestans is poorly studied.

Pyranocoumarins
Wedelolactone 46 (Figure 8) isolated from Eclipta prostrate plants also demonstrated selective inhibition of HIV-1 integrase with IC 50 = 4 µM [71]. It should be noted that wedelolactone is the only coumarin that has activity against HIV integrase. In addition, wedelolactone has weak protease inhibition activity (32.7% at 100 µM) [71]. clauselenins A and C were non-toxic to normal C8166 cells (CC50 > 200 μM), and TI50 was > 689 [48]. Therefore, these compounds can serve as new leads in the development of new antiviral agents. The second group of natural furocoumarins is the coumestans. They are mainly distributed in plants of the Fabaceae family [26,[66][67][68][69] and have a wide spectrum of biological activity [70]. However, the antiviral activity of coumestans is poorly studied.
Wedelolactone 46 (Figure 8) isolated from Eclipta prostrate plants also demonstrated selective inhibition of HIV-1 integrase with IC50 = 4 μM [71]. It should be noted that wedelolactone is the only coumarin that has activity against HIV integrase. In addition, wedelolactone has weak protease inhibition activity (32.7% at 100 μM) [71].  Thus, among furocoumarins, linear coumarins are the largest class of anti-HIV compounds. The antiviral action is mediated by host cell cycle inhibition. The only example of integrase inhibitors is wedelolactone.

Pyranocoumarins
Pyranocoumarins are an important subclass of coumarins with a wide spectrum of biological activity, among which anti-HIV activity can be distinguished [72][73][74].
In this section, linear and angular pyranocoumarins are discussed. Linear pyranocoumarins 47-49 ( Figure 9) isolated from the stems of Clausena lenis [48] and Ficus nervosa [75] demonstrated high to moderate anti-HIV activity in the micromolar range (EC 50 = 1.87-3.19 µM) and TI = 63-107 [54]. As demonstrated by the enzyme assay, the anti-HIV activity of these pyranocoumarins is mediated by RT inhibition [48]. Thus, among furocoumarins, linear coumarins are the largest class of anti-HIV compounds. The antiviral action is mediated by host cell cycle inhibition. The only example of integrase inhibitors is wedelolactone.

Pyranocoumarins
Pyranocoumarins are an important subclass of coumarins with a wide spectrum of biological activity, among which anti-HIV activity can be distinguished [72][73][74].
Subsequently, a systematic study of the SARs of calanolide A analogs led to more active derivatives than parent calanolide A [85,86]. Thus, it was demonstrated that 11demethyl-12-oxo calanolide A 61 (Figure 10), possessing only one chiral center, has similar inhibitory activity against HIV-1 and a better therapeutic index (EC50 = 0.11 μM and TI = 21-169) [87]. 10-Bromomethyl-11-demethyl-12-oxo-calanolide A 62 [85] and 10-chloromethyl-11-demethyl-12-oxo-calanolide A 63 [86] (Figure 10) showed greater anti-HIV-1 activity at the nanomolar level (EC50 = 2.85 nM and TI > 10526 and EC50 = 7.4 nM and TI = 1417, respectively). Compounds 61-63 demonstrate no detectable toxicity [85]. In addition, compound 63 demonstrated a druggable profile with 32.7% oral bioavailability in rats and extremely high potency against the wild-type HIV-1 and Y181C single mutation of HIV-1 [86]. Pyranocoumarin GUT-70 64 (Figure 11) was isolated from Calophyllum brasiliense stem bark [88,89]. It stabilized plasma membrane fluidity, inhibited HIV-1 entry, and down-regulated the expression of chemokine receptors CXCR4, CD4, and CCR5. GUT-70 also had an inhibitory effect on viral replication through the inhibition of NF-κB [90]. Therefore, this compound may be a dual-functional and viral mutation-resistant reagent. Another important feature of this compound is that GUT-70 inhibited HIV-1 replication in both acutely and chronically infected cells [91]. The antiviral activity (determined in several cell lines) and toxicity (MTT assay) of GUT-70 are presented in Table 5. Unfortunately, despite several mechanisms of action, this compound is characterized by low therapeutic indices. Pyranocoumarin GUT-70 64 (Figure 11) was isolated from Calophyllum brasiliense stem bark [88,89]. It stabilized plasma membrane fluidity, inhibited HIV-1 entry, and downregulated the expression of chemokine receptors CXCR4, CD4, and CCR5. GUT-70 also had an inhibitory effect on viral replication through the inhibition of NF-κB [90]. Therefore, this compound may be a dual-functional and viral mutation-resistant reagent. Another important feature of this compound is that GUT-70 inhibited HIV-1 replication in both acutely and chronically infected cells [91]. The antiviral activity (determined in several cell lines) and toxicity (MTT assay) of GUT-70 are presented in Table 5. Unfortunately, despite several mechanisms of action, this compound is characterized by low therapeutic indices.  The seseline scaffold is presented by seselin and suksdorfin-typ genated counterpart.
Lee and colleagues [72] isolated suksdorfin 66 from the fruit which demonstrated inhibition of HIV-1 replication in H9 cells with E  The seseline scaffold is presented by seselin and suksdorfin-type coumarin, its oxygenated counterpart.
Thus, among linear and angular pyranocoumarins, the latter are the most promising in terms of developing anti-HIV agents. These compounds are characterized by good antiviral activity, but they have some solubility problems, which seem to be due to the presence of a condensed ring system.
Prenyl derivatives of simple coumarins, pyranocoumarins and furanocoumarins, are genetically related compounds since the biosynthesis of pyranocoumarins and furanocoumarins occurs through cyclization of the isoprene fragment with the aromatic cycle [95,96]. Furthermore, the mode of action of anti-HIV coumarins is often carried out through identical targets, such as RT inhibition.
The unique structure of coumarins determines their low toxicity compared to other heterocycles and, in combination with effective protocols for coumarin synthesis, provides good potential for developing anti-HIV drugs based on the coumarin scaffold.

Conclusions
Among natural coumarins, there are antiviral compounds with activity against viral enzymes, reverse transcriptase, and integrase. While several types of coumarins (simple coumarins, pyranocoumarins, and furanocoumarins) are active against reverse transcriptase, the only known coumarin with anti-integrase activity is wedelolactone. In addition, simple and angular coumarins are capable of inhibiting cellular factors that regulate HIV-1 replication. Finally, simple coumarins can block the transmission of viral particles from infected macrophages to healthy cells.
Among the anti-HIV coumarin derivatives, the pyranocoumarins-represented by the calanolide and suksdorfin families, as well as simple coumarin C3,C6-diterpenoidsare of the greatest interest. These compounds are characterized by effective inhibition of immunodeficiency virus replication in the nanomolar range, and, in addition, some of them act by several mechanisms. A slight tuning of the structure of the natural compounds allows for obtaining even more active compounds with a therapeutic index of up to 10 8 for the suksdorfin derivatives.
We reviewed the information on the anti-HIV properties of simple coumarins which allows for the consideration of the coumarin cycle as a privileged framework for the search and further development of anti-HIV compounds. Nevertheless, the unique properties are not limited to anti-HIV activities, but they can also target other RNA-based viruses, among which SARS-CoV-2 currently attracts the most significant attention [97].