Introduction

Acquired immunodeficiency syndrome (AIDS) is very severe and life threatening syndrome caused by Human immunodeficiency virus (HIV) (Pironti et al. 2014). HIV is responsible for declining the immunity which leads to various other secondary infection including TB, pneumonia, Herpes etc. (Rodriguez-Penney et al. 2013). HIV-I and HIV-II are two different strains of HIV virus but HIV-I is very common and affected large number of people while HIV-II is restricted to African countries (Degroote et al. 2014). HIV is commonly spread by blood transfusion and sexual transmission (Moore et al. 2014). As per WHO, Asian and African countries have maximum number of patients suffering from AIDS (Group W–H 2003). According to United Nations report, there are around 40 million patients who are living with HIV. A total number of 30 million people have died because of AIDS since its epidemic (https://aidsinfo.unaids.org/). Diagnosis of the HIV virus in the blood is usually done by viral RNA load (Hamarsheh 2020). The infection is associated with an acute symptomatic period that includes fever, general malaise, lymphadenopathy, rash, myalgia and severe consequences like meningitis (Hoenigl et al. 2016). The severity of symptoms is associated with the level of viral load and dependent on host and viral genotype (Basavaraj et al. 2010). During acute infection, higher amount of HIV RNA is present in plasma (Simon et al. 2006). HIV is difficult to diminish completely when it establishes a quiescent or latent infection within the memory CD4 + T cells because of continuous initiation of replication as HIV DNA integrated into host chromatin (Levy et al. 1996). A life cycle of HIV virus requires function of three enzymes including HIV protease, HIV reverse transcriptase and HIV integrase (Kirchhoff 2013; Boireau et al. 2007). HIV reverse transcriptase is responsible to convert single stranded RNA to double stranded DNA (Cihlar and Ray 2010; Vernekar et al. 2015). HIV protease accounts for formation of functional protein from large polypeptide chain (Patel and Bhatt 2020; Ghosh et al. 2016; Xu et al. 2019). The integration of HIV virus into human genome is carried out by HIV integrase enzyme (Bhatt et al. 2014a; Patel et al. 2016). CXCR4 (C-X-C Motif Chemokine Receptor 4), CCR5 (C–C chemokine receptor type 5) and fusion inhibitors are the other emerging targets to treat HIV apart from three enzymes (Cagigi et al. 2008). Life cycle of HIV replication is depicted in Fig. 1.

Fig. 1
figure 1

Life cycle of HIV virus

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The current treatment of AIDS is antiretroviral therapy (ART), comprises of combination therapy of reverse transcriptase inhibitor with protease or integrase inhibitor (Pelay-Gimeno et al. 2015). All these enzymes as well as receptors have been targeted and repressed by many drugs in last three decades but they have many problems like resistance and severe side effects (Bartlett and Shao 2009). Natural phytoconstituents are alternatives for the treatment of many diseases. There are various herbal drugs which have been used in diseases like digoxin in treatment of congestive heart failure, reserpine as antihypertensive, vincristine as antineoplastic, and artemisinin as antimalarial. Natural phytoconstituents do not have problems of severe side effects and drug resistance. Various phytoconstituents identified in recent years have shown different pharmacological properties. Thus, this review focuses on natural phytoconstituents with effective anti-HIV properties and the promising phytoconstituents were classified based on their mechanism of action (Yadav et al. 2017).

In this review, a complete survey of the tropical medicinal plants with their anti-HIV benefits are reviewed based on the mechanism of action. Medicinal plants are classified as Reverse transcriptase (RT) inhibitors, Protease (PR) inhibitors, Integrase (IN) inhibitors, cell fusion inhibitors, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) inhibitors and multi-targeted acting medicinal plants. Moreover, phytoconstituents and biological activity of all the plants have been incorporated. Authentic sources of information were taken for resolving taxonomy, plant distribution and other related information (https://indiabiodiversity.org/; https://eol.org/). Scientific articles from the year 1970 to 2021 were taken from the electronic databases i.e., Pubmed, Science Direct, Google Scholar, Web of Science and Scopus. The terms used for this review included anti-HIV agents, all the botanical names and synonyms of the species, phytoconstituents present in each plant, and biological activity of each medicinal plant.

Tropical medicinal plants used against HIV

Reverse transcriptase (RT) inhibitors

Reverse transcriptase inhibitors or Anti-RT drugs act on reverse transcription of the HIV by inhibiting reverse transcriptase enzyme. These drugs inhibit the formation of viral DNA and restrict the expansion of the HIV throughout the body (Maartens et al. 2014). Indian herbal plants namely Justicia Gendarussa Burm.F., Acorus Calamus L., Allium Sativum L., Hemidesmus Indicus (L.) R. Br, Canna Indica L., Anogeissus Acuminata (Roxb. ex DC.) Guill., Perr. & A. Rich., Swertia Franchetiana, Vitex Trifolia L., Artocarpus Heterophyllus Lam., and Plumbago Indica L. are reported to have anti-RT benefits. The active chemical constituents of these medicinal plants are summarized in this review.

Justicia Gendarussa Burm.F.

Justicia Gendarussa is native to tropical Asia. In India, it is found in Kerala, Tamil Nadu, Assam and Maharashtra. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani and Traditional Chinese medicine. It has several common names in India such as Water Willow, Kala Bashimb, Nili Nargand, Indrani and Kapika (https://indiabiodiversity.org/). Aerial part of this plant has RT inhibitory activity for treating HIV/AIDS. Crude extract of this plant exhibited potent HIV-1 RT inhibition activity in in vitro studies (Woradulayapinij et al. 2005). Crude extract of aerial part contains mixture of phytosterol and flavonoids such as β-sitosterol, β-sitosterol-β-D-glycoside and Aromadendrin. Crude water extract of Justicia Gendurussa showed anti-RT activity by acting on reverse transcription of the viral RNA genome at the concentration of 200 µg/ml with inhibition ratio (relative % inhibition [IR]) higher than 90% (Maartens et al. 2014; Woradulayapinij et al. 2005).

Acorus Calamus L.

Acorus calamus L. is obtained from the north temperate hemisphere and tropical Asia. In India, it is distributed mainly in Kerala, Punjab, and Assam. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine, Sowa-Rigpa, and modern medicine. It is also known as sweet root and Gorbach. Rhizome of this plant showed activity against HIV/AIDS (Salehi et al. 2018). In vitro studies of this plant revealed that crude hexane extract has very strong HIV-1 RT inhibition activity with IC50 of 33.96 µg/ml (Silprasit et al. 2011). The crude rhizome part contains alkaloids, flavonoids, gums, lectins, mucilage, phenols, quinone, saponins, sugars, tannins, and triterpenes (steroids).

Allium Sativum L.

Allium Sativum is commonly known as Garlic. It is native throughout India. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Homoeopathy, Traditional Chinese medicine, Sowa-Rigpa, and Modern medicine. It is reported that bulb of garlic has HIV-RT inhibitory activity (Silprasit et al. 2011). Crude hexane extract of the garlic showed > 80% relative inhibition (Silprasit et al. 2011). Crude extract of this plant contains bioactive compounds like Alliin, Allicin, (E)-ajoene, Allyl sulfide, (Z)-ajoene, and 1,2-vinyldithiin (Martins et al. 2016).

Hemidesmus Indicus (L.) R. Br

Hemidesmus Indicus is known as Indian Sarsaparilla or Anantmul. In India, it is mainly distributed in Maharashtra, Tamil Nadu, Kerala, Karnataka, Meghalaya and Assam. Roots of the Hemidesmus Indicus has potent HIV-RT inhibitory activity. Crude extract mainly contains various bioactive compounds such as two pentacyclic triterpenoic derivatives, Lupeol and Lupeol acetate. 2-hydroxy-4-methoxybenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzoic acid, caffeic acid, chlorogenic acid and β- amyrin acetate can also be obtained from the crude extract. Lupeol has promising effect on RNA dependent DNA polymerase (RDDP) enzyme and RNase H function against HIV-RT with IC50 of > 100 µM and 11.6 µM, respectively (Esposito et al. 2017). Lupeol acetate also showed activity against RDDP and RNase H with IC50 of 100 µM and 63 µM, respectively. Lupeol and its acetate bind with allosteric site of the RNase H and exhibit inhibition activity. Studies on decoction of Hemidesmus Indicus indicated the inhibitory action against RNase H and RDDP enzyme with IC50 values of 3 and 7 μg/ml, respectively (Esposito et al. 2017).

Canna Indica L.

Canna Indica is known as Indian shot and canna lily. It is native throughout India, Sri Lanka and Malaysia. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha and Traditional Chinese medicine. Canna Indica L. belongs to family Cannaceae. It is reported that Rhizome of this plant has potent anti-RT activity against AIDS/HIV (Woradulayapinij et al. 2005). Crude water extract of this plant showed 92% IR at 200 µg/ml (Woradulayapinij et al. 2005). Crude extract of Canna contains polar compounds like polyphenolics (flavonoids, tannins), triterpenoids, steroids and some sugars (Kumbhar et al. 2018).

Anogeissus Acuminata (Roxb. ex DC.) Guill., Perr. & A. Rich.

Anogeissus Acuminata is a tree of Combretaceae family (Rimando et al. 1994). It is generally known as Button tree and Dhaura. It is widely distributed in India. Chemical constituents of this plant i.e., Anolignan A and Anolignan B have potent action on the reverse transcription of retrovirus. Generally, Anolignan A and Anolignan are given in combination. HIV-1 RT IC50 (µg/ml) of Anolignans A and B in combination is 30–50 µg/ml and percentage inhibition is more than 90% (Rimando et al. 1994).

Swertia Franchetiana

Swertia Franchetiana is the Indian medicinal plant also known as Panicled Swertia. It belongs to Gentianaceae family. It is used in Ayurveda medicinal system. It has notable action on reverse transcriptase enzyme of HIV (Pengsuparp et al. 1995). One of the constituents, Xanthone (extracted out from the root of Swertia Franchetiana) showed promising anti-RT action in the reported studies. Swertifrancheside and Swertipunicoside are the active phytoconstituents of this plant. These constituents showed inhibition of reverse transcription at ED50 of 30.9 µg/ml and 3.0 µg/ml for Swertifrancheside and Swertipunicoside, respectively (Pengsuparp et al. 1995; Wang et al. 1994).

Vitex Trifolia L.

Vitex trifolia L. is well known as Arabian Lilac. It is cultivated in South India and Assam. It is a tree of Lamiaceae family (Woradulayapinij et al. 2005). It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine and Sowa-Rigpa. Arial part of this tree has very strong anti-RT action. Crude water extract of Vitex trifolia has 98.06% inhibition against reverse transcription at 200 µg/ml (Woradulayapinij et al. 2005). Crude extract of aerial part of this medicinal plant contains polyphenolic compounds, flavonoids, proteins, tannins, phytosterols, and saponins. Several monoterpenes along with diterpenes, dihydrosolidagenone, beta-sitosterol-3-O-glucoside, terpineol, alpha-pinene, 3,6,7-trimethylquercetagetin, hexanic and dichloromethanic can also be extracted from the stem (Suchitra and Cheriyan 2018).

Artocarpus Heterophyllus Lam.

Artocarpus Heterophyllus Lam. is generally known as Jack Fruit and it is well known as Katahal in India. This plant belongs to Moraceae family. It is obtained from Jammu and Kashmir, Himachal Pradesh, and Sikkim. Artocarpus Heterophyllus is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani and Traditional Chinese medicine. Crude extract of seeds of jackfruit showed very potent and strong inhibitory effect against HIV-1 RT with > 80% IR at 0.225 mg/ml (Silprasit et al. 2011). Crude extract of jackfruit seed contains protein, calcium, iron, Tiamine, carbohydrates specially starch and various phytochemicals such as phenolic compounds, flavonoids, tannins and saponins. Seeds have three phenolic acids, viz., gallilc acid, tannic acid, and ferulic acid (Ranasinghe et al. 2019).

Plumbago Indica L.

Plumbago Indica belongs to Plumbaginaceae family. It is cultivated in South East Asia. In India, it is obtained mainly from Kerala and Tamil Nadu. It is commonly known as Fire plant, Radix Plumbago, and Chitrakmool. Root of this plant is used to treat AIDS/HIV-1 (Silprasit et al. 2011). Study on the crude extract of root showed potent anti-RT action with more than 80% IR at 0.255 mg/ml (Silprasit et al. 2011). Crude extract contains napthoquinone specially plumbagin, which has greater medicinal benefits. Crude plant extract also contains some phytochemicals like palmitic acid, myricyl palmitate, plumbagic acid, lactone, ayanin, and azalenin (Dinda et al. 2019). The phytoconstituents having HIV-RT inhibitory activities are given in Table 1.

Table 1 Chemical structures of phytoconstituents having HIV reverse transcriptase inhibitory activity
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Protease inhibitors (anti-PR drugs)

Protease inhibitors or anti-PR drugs act on the formation of viral protein of the HIV by inhibiting protease enzyme (Maartens et al. 2014). Due to protease inhibition, envelop protein and other proteins cannot be formed and therefore spreading of the infection throughout the body can be controlled. Tropical herbal plants and their chemical constituents which are most active and potent reviewed below.

Areca Catechu L.

It is known as Supari and Areca palm in India. It is mainly cultivated in Arunachal Pradesh, Assam, Manipur, and Meghalaya in India. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine, Sowa-Rigpa, and Modern medicine (https://indiabiodiversity.org/). Seeds of the plants are reported to have activity against HIV (Kusumoto et al. 1995). Crude extract from the seeds of Areca Catechu showed very potent HIV-PR inhibitory activity (Kusumoto et al. 1995). Water and methanol crude extracts also exhibited inhibition of protease enzyme. % inhibition of protease enzyme for water and methanol crude extract was found to be 71.5 ± 1.5% and 84.1 ± 0.7%, respectively at the concentration of 0.2 mg/mL (Kusumoto et al. 1995). Crude extract of the plant contains mainly three areca tannins viz. Procyanidin B1, Arecatannin A1 and Arecatannin B1 (Pelay-Gimeno et al. 2015). ( +)-Catechin, (−)-Epicatechin, (−)-Epicatechin gallate and (−)-Epigallocatechin gallate are also found in the crude extract of the plant. Arecatannin A1 and B1 both showed inhibition of the protease enzyme at an IC50 of 0.5 mM (Kusumoto et al. 1995).

Terminalia Arjuna

Terminalia Arjuna belongs to Combretaceae family and it is better known as Arjun tree in India. It is easily available in India and Sri Lanka. It is used in the several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine, and Sowa-Rigpa. HIV-PR inhibitory activity is reported for the stem bark of the Arjun tree. Crude extract of the stem bark is used to treat HIV (Kusumoto et al. 1995; Xu et al. 1996; Sabde et al. 2011). Water crude extract and methanol crude extract of the Arjun stem bark showed HIV-PR inhibition with 80% and 83%, respectively at the concentration of 0.2 mg/ml (Kusumoto et al. 1995; Xu et al. 1996). Crude extract of the Arjun stem bark contains terpenes such as Triterpenoids, and Ursane triterpenoids. It also contains other phytochemicals like Glycosides, Flavonoids, Phenolics, and Tannins (Sabde et al. 2011; Amalraj and Gopi 2017). Among all the phytoconstituents, terpenes have significant action on the HIV-PR (Amalraj and Gopi 2017). Crude extract of the Arjun stem bark contains several Triterpenes like Arjunin (Amalraj and Gopi 2017; Row et al. 1970), Arjunic acid (Amalraj and Gopi 2017; Row et al. 1970), Arjungenin (Amalraj and Gopi 2017; Honda et al. 1976; Singh et al. 2002a, 2002b), Terminic acid (Amalraj and Gopi 2017; Anjaneyulu and Prasad 1983), Terminoltin (Amalraj and Gopi 2017; Singh et al. 1995) and Arjunolic acid (Amalraj and Gopi 2017; Singh et al. 2002a, 2002b; Wang et al. 2010). Ursane triterpenoids namely, 2α,3β-dihydroyurs-12,18-oic acid 28-O-β-D-glucopyranosyl ester, 2α,3β,23-trihydroxyurs-12,18-dien-28-oic acid 28-O-β-glucopyranosyl ester, Qudranoside VIII, Kajiichigoside F1; 2α,3β,23-trihydroxyurs-23-trihydroxyurs-12,19-dien-28-oic acid 28-O-β-D-glucopyranosyl ester type of phytochemicals are also present in the extract (Amalraj and Gopi 2017; Singh et al. 2002b).

Acacia Catechu

Acacia catechu is commonly known as Catechu, Cachou and Black cutch (Modi et al. 2013; Li et al. 2010). It is mainly cultivated in East, Central, South and North Indian states such as Tamil Nadu, Karnataka, Maharashtra, Andhra Pradesh, Gujarat, Madhya Pradesh, Uttar Pradesh and Rajasthan (Modi et al. 2013). It is a tree of Fabaceae family. It is used in the several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani and Traditional Chinese medicine. Several compounds have been isolated from Acacia Catechu such as 4-hydroxybenzoic acid, Kaempferol, Quercetin, 3, 4’, 7-trihydroxyl-3′,5-dimethoxyflavone, Catechin, Rutin, Isorhamnetin, Epicatechin, Afzelechin, Epiafzelechin, Mesquitol, Ophioglonin, Aromadendrin and Phenol. Among these chemical constituents, Catechin, Rutin and Isorhamnetin have antioxidant property by scavenging free radicals (Modi et al. 2013; Li et al. 2010; Li et al. 2011). Flavonoids of this plant have promising anti-inflammatory activity and immunomodulatory activity (Modi et al. 2013; Li et al. 2011). Resin of the stem bark has significant inhibitory activity of HIV-PR. Studies reported that crude n-butanol fraction of this plant showed very potent activity against HIV-PR with an IC50 of 12.9 µg/ml at the concentration of 50 µg/ml (Modi et al. 2013). Catechin and Epicatechin showed significant protease inhibitory activity at an IC50 of 0.60 µg/ml and CC50 of 950 µg/ml (Modi et al. 2013).

Acacia Nilotica (L.)

Acacia Nilotica is well distributed in India and mostly known as Babul. Babul tree is also known as Gum Arabic tree. This plant belongs to family Fabaceae (Hussein et al. 1999). Studies on HIV-PR are reported for the stem bark and pods of this plant. Methanol crude extract of Nilotica pods exhibited activity against HIV-PR with an IC50 of 57 µg/ml. Water crude extract of Nilotica pods showed HIV-PR inhibition with an IC50 of 48 µg/ml. Tannins are present in the plant extract which are having promising biological activities along with HIV-PR inhibition activity (Hussein et al. 1999). Crude extract of this plant also contains terpenoids, tannins, alkaloids, saponins and glycosides (Hegde et al. 2017).

Saraca Indica

Saraca Indica is well known as Ashok tree and Asopalva. This tree belongs to Fabaceae family. The Ashok tree is mainly cultivated in Kerala, Tamil Nadu, and Gujarat. Stem bark of Ashok tree is reported for the activity against HIV-PR (Kusumoto et al. 1995). Crude aqueous extract of this plant has very strong activity against HIV-PR with 84% inhibition at the concentration of 0.2 mg/ml (Kusumoto et al. 1995). Crude extract of Ashoka contains main chemical constituents such as (+)-Catechin (CAT), (−)-Epicatechin (EPI), Procyanidin B-2, 11’-deoxyprocyanidin B4, and Leucocyanidin (Tandon and Yadav 2017; Senapati et al. 2012; Srivastava et al. 1988; Shirolkar et al. 2013).

Plectranthus Barbatus Andrews

Plectranthus Barbatus is a folk medicine from Lamiaceae family. It is known as Pashan Bhedi, and Patharchur. Global distribution of this plant is in India, Sri Lanka, and Tropical East Africa. Generally, it is cultivated from Tamil Nadu and Maharashtra. Leaves of this plant has promising activity against several enzymes mainly protease enzyme (Kapewangolo et al. 2013). Crude ethanolic extract of Plectranthus Barbatus showed dose dependent activity against HIV-PR (Kapewangolo et al. 2013). P. Barbatus inhibited the enzyme HIV-PR with an IC50 of 62.0 ± 0.2 µg/ml. Inhibition of HIV-1-PR could be attributed to some diterpenoid compounds present in this plant (Kapewangolo et al. 2013; Alasbahi and Melzig 2010a, 2010b). This plant has potential to inhibit inflammatory cytokines (Kapewangolo et al. 2013). A diterpenoid, Isoforskolin is isolated from the Plentracthus Barbatus leaf (Haque et al. 2015).

Punica granatum L.

Punica granatum L. is well known as pomegranate. It is cultivated throughout Assam, Kashmir, and Maharastra. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine, and Sowa-Rigna. This plant belongs to family Lythraceae (Kusumoto et al. 1995). Crude aqueous extract of pomegranate from the root bark showed 88% inhibition of HIV-PR at 250 µg/ml concentration (Kusumoto et al. 1995; Xu et al. 1996). Crude extract of the pomegranate root bark (pericarp) contains tannins such as Gallic acid, Granatin A, Corilagin and Ellagic acid. The Pomegranate fruit contains Ellagitanin and Ellagic acid (Alasbahi and Melzig 2010b).

Adansonia Digitata L.

Adansonia Digitata L. has several common names in India such as Gorakh Imli, Brahmamlika, Bottle tree and Dead rat tree. It is cultivated mainly in Maharashtra and Gujarat. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, and Unani. This plant belongs to Malvaceae family. It is one of the largest and reportedly longest living species of the world (Sharma and Rangari 2016). Leaf and fruit pulps of bottle tree have significant action against HIV-PR (Sharma and Rangari 2016). Crude ethanolic leaf extract of bottle tree showed 75% inhibition of HIV-PR at the concentration of 50 µg/ml. Importantly, Fruit pulp extract of this plant exhibited 74% inhibition of HIV-PR at the concentration of 50 µg/ml (Sharma and Rangari 2016). Crude extract contains vitamin C, sugar, potassium tartrate and calcium. Leaves of this plant are rich in phenolic compounds with several other chemical constituents such as Procyanidin, O-glycosides of Apigenin, Quercetin (Quercetin glycoside, Rutin, Quercetin pentoside, Quercetin 3-hydroxy-3-methylglutaryl-O-hexoside), Kaempferol derivatives, C-glycoside Vitexin or Isovitexin, and Aglycone quercetin (Braca et al. 2018).

Andrographis Paniculata

Andrographis Paniculata belongs to family Acanthaceae. It is well known as Andrographis and Kalmegh. It is cultivated in India and Sri Lanka. In India, it is cultivated in Assam, Kerala, Gujarat, Madhya Pradesh, and Odisha. Aerial part of Kalmegh reported to have significant inhibition of HIV-PR (Niranjan Reddy et al. 2005). Novel Bis-andrographolide ether, Andrographolide, 14-deoxy-11,12-didehydroandrographolide, Andrograpanin, 14-deoxyandrographolide, (±)-5-hydroxy-7,8-dimethoxyflavanone, and 5-hydroxy-7,8-dimethoxyflavone have been isolated from the aerial parts of Andrographis Paniculata and their structures were established by spectral data (Niranjan Reddy et al. 2005). Among these compounds, Andrographolide (EC50 = 49.0 µg/mL) and 14-deoxy-11,12-didehydroandrographolide (EC50 = 56.8 µg/mL) showed significant anti-HIV activity (Niranjan Reddy et al. 2005). A comprehensive list of phytoconstituents having HIV-PR inhibitory activities are given in Table 2.

Table 2 Chemical structures of phytoconstituents having HIV protease inhibitory activity
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Integrase inhibitors (anti-IN drugs)

HIV-IN inhibitors or anti-IN drugs inhibit the enzyme integrase. IN inhibitors act on HIV double stranded DNA and inhibit the formation of proviral RNA in cell nucleus (Maartens et al. 2014). By this mechanism, IN inhibitors prevent incorporation of HIV into host genome. Indian herbal plants and their chemical constituents with HIV-IN inhibitory activities are reviewed below.

Dioscorea bulbifera L.

Dioscorea bulbifera L. belongs to family Dioscoreaceae. It is also known as Air Potato and Ratalu. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, Unani, Traditional Chinese medicine and Sowa-Rigpa. It is globally distributed on Paleotropics and mainly cultivated in Maharashtra, Karnataka, Kerala, Tamil Nadu, etc. It is the traditional Indian and Chinese medicinal plant (Chaniad et al. 2016). It is used for sore throat, gastric cancer, carcinoma of the rectum and many other diseases. Reported literature suggested that air potato has inhibitory action against HIV-IN (Chaniad et al. 2016). Air Potato contains Allantoin, 2,4,30,50-tetrahydroxybibenzyl, 2,4,6,7-tetrahydroxy-9,10-dihydrophenanthrene, Myricetin, 5,7,40-trihydroxy-2-styrylchromone, Quercetin-3-O-β-D-glucopyranoside, and Quercetin-3-O-β-D-galactopyranoside. Among these compounds, Myricetin has the most potent inhibitory action with IC50 value of 3.15 µM (Chaniad et al. 2016). 2,4,6,7-tetrahydroxy-9,10-dihydrophenanthrene, Quercetin-3-O-β-D-glucopyranoside, and Quercetin-3-O-β-D-galactopyranoside showed HIV-IN inhibition with IC50 of 14.20 µM, 19.39 µM and 21.80 µM, respectively (Chaniad et al. 2016).

Albizia procera (Roxb.) Benth.

Albizia procera belongs to the family Fabaceae and it is also known as White siris tree. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, and Unani. It is easily available in Andaman & Nicobar Island, Assam, Madhya Pradesh, Meghalaya, Odisha, Uttar Pradesh, etc. Bark of white siris tree has promising HIV-IN inhibitory activity (Bunluepuech and Tewtrakul* 2011). Crude water extract of bark showed potent inhibitory activity against HIV-IN with the IC50 of 5.9 µg/ml. HIV-IN inhibition was reported for the two main phytoconsituents, (+)-Catechin and Protocatechuic acid of the bark extract (Bunluepuech and Tewtrakul* 2011; Panthong et al. 2015).

Aglaia lawii (Wight) C.J. Saldanha

Aglaia lawii is also known as Karakil. This plant belongs to Meliaceae family. In India, it is mainly cultivated in Kerala and Maharashtra. Leaves of this plant is reported for HIV-IN activity. Crude extract of leaves contains several phytochemicals such as Retusin, Pachypodol, (−)-Yangambin, Pyramidatine, 24-epi-piscidinol A, Aglaiodiol, Cycloart-23E-ene-3β-25-diol, Pyramidaglain A, Pyramidaglain B, and N-methyl-trans-4-hydroxy-L-proline. Among these compounds, N-methyl-trans-4-hydroxy-L-proline has very potent anti HIV-IN effects with an IC50 of value 11.8 µg/ml (Puripattanavong et al. 2016).

Toddalia asiatica (L.) Lam.

Toddalia asiatica L. is known as Forest pepper and it belongs to family Rutaceae. It is used in several systems of medicine such as Folk medicine, Ayurveda, Sidhha, and Traditional Chinese Medicine. It is cultivated in Kerala, Karnataka, Tamil Nadu, and Assam. Root extract of this plant contains Benzo[c]phenanthridine alkaloids, Quinoline alkaloids, and Coumarin derivatives (Rashid et al. 1995). Among these compounds, Nitidine (quaternary benzo[c]phenanthridine alkaloid) and Magnoflorine (Aporphinoid alkaloid) showed potent anti-HIV-IN activity. Nitidine efficiently inhibited the HIV-IN at a concentration range of 1–10 µg/ml (Rashid et al. 1995). The phytoconstituents having HIV-IN inhibitory activities are given in Table 3.

Table 3 Chemical structures of phytoconstituents having HIV integrase inhibitory activity
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Cell fusion inhibitors

HIV envelope glycoprotein (Env) comprises of gp120 and gp41subunits. Among these subunits gp120 binds to the CD4 receptor. This causes conformational changes in Env and it reveals the binding site for co-receptor (chemokine). This initiates the membrane fusion process as the fusion peptide of gp41 inserts into the target membrane, followed by six-helix bundle formation and complete membrane fusion (Wilen et al. 2012; Zaitseva et al. 2017). Some medicinal plant extracts are able to inhibit the HIV cell entry by inhibiting cell fusion. Medicinal plants targeting cell fusion are reviewed as below.

Ailanthus altissima (Mill.) Swingle

Ailannthus altissima is commonly named as Ailanto or Tree of heaven. Ailanto is from Simaroubaceae family. It is used in several systems of medicine such as Folk medicine, Homeopathy and Traditional Chinese Medicine. It is cultivated in India and China. In India, this plant is distributed in Haryana, Himachal Pradesh, Kashmir, Assam, Punjab and Uttar Pradesh. Stem bark of this medicinal plant has cell fusion inhibitory activity. Methanol crude extract of this plant exhibited virus–cell fusion inhibitory activity with 74.9% inhibition (Chang and Woo 2003). Stem bark of Ailanto tree consists of Coumarin and Triterpenoid derivatives. Among these derivatives, Tetracyclic triterpenoids (Altissimanins A-E) has promising action against HIV cell fusion (Al-Snafi 2015; Hong et al. 2013).

Jatropha curcas L.

Jatropha curcas L. is a shrub known as Physic nut and Jangli Arandi. In India, it is cultivated in Andhra Pradesh, Assam, Bihar, Madhya Pradesh, Maharastra, Rajasthan, Tamil Nadu, and Uttar Pradesh. It is used in several systems of medicine such as Ayurveda, Folk medicine, Homoeopathy, Unani, Siddha, and Traditional Chinese medicine (Muanza et al. 1995; Matsuse et al. 1998). This shrub belongs to family Euphorbiaceae. 5,7-dimethoxycoumarin and 6,7-dimethoxycoumarin obtained from methanolic leaf extract showed moderate inhibition of HIV-1-induced cytopathic effect (IC50 = 9 µg/ml) with low cytotoxicity (Muanza et al. 1995; Matsuse et al. 1998).

Momordica charantia L.

Momordica charantia L. is also known as bitter gourd. It belongs to Cucurbitaceae family. It is used in several systems of medicine such as Ayurveda, Folk medicine, Homoeopathy, Unani, Siddha, Traditional Chinese medicine, and Sowa Rigpa. It is cultivated in Assam, Maharashtra, Gujarat, Tamil Nadu, Rajasthan, and Uttar Pradesh. Seed and fruit extracts of this plants are reported for the inhibition of syncytium formation. MAP 30 protein can be isolated from the fruits and seeds of the plant. MAP-30 protein showed 60% and 86% inhibition of syncytium formation at 1.67 nM and 1670 nM, respectively (Lee-Huang et al. 1991).

Anisomeles indica (L.) Kuntze

Anisomeles indica L. is mainly cultivated in Assam and Meghalaya. It is known as Kala Bhangra. It is used in several systems of medicine such as Folk medicine and Traditional Chinese medicine. Ovatodiolide a diterpenoid from Anisomeles indica showed potent anti-HIV activity with maximum cellular protection of 80–90%. Ovatodiolide inhibited cytopathic effects at an IC50 of 1.20 µg/ml (Bodiwala et al. 2009). List of phytoconstituents having HIV fusion inhibitory activity are mentioned in Table 4.

Table 4 Chemical structures of phytoconstituents having HIV fusion inhibitory activity
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CCR5 and CXCR4 inhibitors:

The viral entry consists of complex sequence of events mediated by cellular membrane protein which interacts with viral glycoprotein gp120 and CD4 cellular receptor. Further interaction of such glycoprotein with any of the two co-receptors CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 promote appropriate conformational modification during an early stage of the viral cycle (Dragic et al. 1996; Scarlatti et al. 1997). Recently, CCR5 and CXCR4 antagonist is suggested by the identification of viral stain tropism for clinical use. It inhibits the entry of virus (Kalinina et al. 2013). Some medicinal plant extracts are able to inhibit the HIV cell entry by inhibiting co-receptor CCR5 and CXCR4. Those medicinal plants is given below and in Table 5.

Table 5 Chemical structures of phytoconstituents having CCR5 and CXCR4 inhibitory activity
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Avicennia marina var. rumphiana (Hallier f.) Bakh.

Avicennia marina is an Indian medicinal plant known as Gray mangrove. It is mainly distributed in Paleotropics. In India, it is cultivated in Kerala and Maharashtra. It is used in Folk medicine system. Iridoid glycoside namely 2’-O-(4- methoxycinnamoyl)mussaenosidic acid isolated from Avicennia marina showed CCR5 and CXCR4 inhibitory activity. Methanolic seed extract of 2’-O-(4-methoxycinnamoyl)mussaenosidic acid is reported to inhibit the entry of retro virus through CCR5 and CXCR4 inhibition with 99% inhibition and EC50 of 0.1 µg/ml (Behbahani 2014; Feng et al. 2006).

Multi- target acting medicinal plants

A multi-target or hybrid drug can be defined as a chemical entity that combines the pharmacophores of two or more drugs with different mechanisms of action in a single molecule which is capable to interact simultaneously with two or more molecular targets (Castro and Camarasa 2018). Some of the medicinal plants with multi-targeted potencies for the treatment of HIV are reviewed below.

Arctium lappa L.

Arctium lappa L. belongs to Asteraceae family and it is known as Greater Burdock. It is used in several systems of medicine such as Folk medicine, Homoeopathy and Traditional Chinese medicine. Arctium lappa L. is generally used for skin diseases such as acne. It is cultivated from Middle East to India, China, Russia, Nepal, Afghanistan and Pakistan. Aerial part of Burdock has multi-targeted action against HIV. Burdock possesses anti-PR, anti-IN and cell fusion inhibition activity (Lam et al. 2000). Aqueous extract of Arctium lappa L. showed inhibitory activity against HIV-IN with 60% inhibition (Au et al. 2001). Results of cell fusion inhibitory activity indicated that 0% HIV antigen positive cells were present when cells were treated with the extract of this plant (Chang and Yeung 1988). Flavonoids and terpenes isolated from roots and leaves showed inhibitory activity against HIV-IN. Luteolin, Quercetin and Rutin are the flavonoids extracted from roots and leaves of Arctium lappa L. Various sesquiterpenes, sesquiterpene lactones and triterpenes can also be extracted from roots and leaves of this plant (Tobyn et al. 2000).

Senecio scandens

Senecio scandens belongs to Asteraceae family. It is easily cultivated in Indian subcontinent, South China, Philippines and Japan. It is used in several systems of medicine such as Folk medicine and Traditional Chinese medicine. It has multi-targeted action against HIV-PR and HIV-IN (Lam et al. 2000; Au et al. 2001). crude methanol and aqueous extract of the whole plant showed % HIV-PR inhibition with 83% and 81%, respectively (200 µg/ml concentration) (Lam et al. 2000). It elicited 60% inhibition of HIV-1 integrase activity at 50 µg/ml (Chang and Yeung 1988). β-sitosterol, pentacosanoic acid, 19α-H lupeone are also effective for HIV inhibitory activity (Wang et al. 2011).

Calophyllum inophyllum L.

Calophyllum inophyllum L. is known as Indian laurel or Alexandrian laurel. It is a tree from Clusiaceae family. General habitat of this tree is terrestrial. It is cultivated in Cambodia, China, India, Indonesia, Japan, Malaysia, Philippines, Sri Lanka, Thailand, Vietnam, Madagascar and Australasia. In India, it is obtained from Andaman and Nicobar Islands, Lakshadweep, Karnataka, Kerala, Odisha, Maharashtra and Tamil Nadu. It is used in Ayurvedic, Siddha and folk medicines, for treating eczema, insanity, syphilis and inflamed eyes. ‘Tacamahaca’ gum from wounded bark is used as purgative and emetic. Calophyllum inophyllum has multi-targeting potential with anti-RT, anti-PR, and anti-IN activity (Narayan et al. 2011). Bark extract of this plant has very potent activity against HIV-IN and HIV-PR. Aqueous extract showed potent inhibitory action against HIV-IN with more than 90% inhibition (IC50 = 5.6 µg/ml). Ethanolic extract also showed more than 90% of HIV-IN inhibition with an IC50 of 9.8 µg/ml. HIV-PR inhibition was observed in aqueous extract and ethanolic extract with IC50 of 16.3 µg/ml and 63.8 µg/ml, respectively (Pawar et al. 2007). Inophyllum B (IC50 = 0.038 µM) and Inophyllum P (IC50 = 0.130 µM) are pyranocoumarins having inhibitory activity against HIV-RT with more than 90% inhibition (Laure et al. 2008; Patil et al. 1993).

Terminalia chebula Retz.

Terminalia chebula Retz. Belongs to Combretaceae family. It is known as black myrobalan. In Gujarat it is commonly known as Harade. It is used in several systems of medicine such as Ayurveda, Folk medicine, Homoeopathy, Unani, Siddha, Traditional Chinese medicine, and Sowa Rigpa. It is cultivated in Andhra Pradesh, Bihar, Gujarat, Himachal Pradesh, Karnataka, Kerala, Madhya Pradesh, Mahrastra, Odisha, Sikkim, Tamil Nadu, Tripura, Uttar Pradesh, and West Bengal. Terminalia chebula has multi-target inhibitory activity against HIV-RT, HIV-PR, and HIV-IN (Kumbhar et al. 2018). Fruit extract of this plant showed promising inhibitory action against HIV-RT, HIV-PR, and HIV-IN. Methanolic and aqueous fruit extract of the plant showed HIV-RT inhibitory activity with IC50 values of 2 µg/ml and 6 µg/ml, respectively (El-Mekkawy et al. 1995). Aqueous and methanolic, both the extracts of fruit showed 50% HIV-PR inhibition at a concentration of 0.2 mg/ml (Kusumoto et al. 1995). T. chebula has moderate HIV-IN inhibition with IC50 value of 10.3 µg/ml. Phytoconstituents of T. Chebula i.e., Gallic acid, 1,3,6-tri-O-galloyl-β-D-glucopyranose, 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose, and Chebulagic acid are promising agents for the treatment of HIV infection (Ahn et al. 2002).

Prunella vulgaris L.

Prunella vulgaris L. is knows as self-heal plant and belongs to the family Lamiaceae. It is used in several systems of medicine such as Folk medicine and Traditional Chinese medicine. It is cultivated in north temperate of Indian subcontinent, Europe, America, Australia and Sri Lanka. This plant has HIV-PR, HIV-IN and cell fusion inhibitory activity by interaction of viral gp120 with cell surface receptor, CD4 (Lam et al. 2000; Yao et al. 1992). Aqueous extract of whole plant showed activity against HIV-PR with 93% inhibition at a concentration of 200 mg/ml (Lam et al. 2000). Aqueous extract of this plant showed moderate inhibition of HIV-IN with an EC50 of 45 µg/ml (Au et al. 2001). P. Vulgaris extract also inhibited gp120-CD4 binding at Ki value of 2 µg/ml (Yao et al. 1992; Tabba et al. 1989). Triterpenes, flavonoids, and some of polyphenols with polysaccharide are promising phyoconstituents for the treatment of HIV infection (Gu et al. 2013; Oh et al. 2011). Triterpenoids are extracted from leaves and stem of P. vulgaris. Betulinic acid and 2α,3α-dihydroxyurs-12-en-28-oic acid are triterpenoids extracted from the leaves and stem of P. vulgaris have anti-HIV activity (Psotová et al. 2003; Kojima and Ogura 1986; Ryu et al. 1992).

Rosa damascena Mill.

Rosa damascena Mill. is known as Damask Rose belongs to Rosaceae family. It is cultivated in Maharashtra, Assam, and Meghalaya. It is used in various systems of medicine such as Ayurveda, Folk medicine, Homoeopathy, Unani and Siddha (Mahmood et al. 1996). Flavonoids have been shown to inhibit various Kaempferol and Quercetin reduced HIV infection by greater than 99% with EC50 of 0.8 µg/ml and 10 µg/ml, respectively (Mahmood et al. 1996; Nakane et al. 1991). Quercetin inhibited CD4/gp120 interaction, HIV-RT and HIV-PR activities. Kaempferol showed anti-HIV-PR activity with an IC50 of 2 µg/ml (Mahmood et al. 1996; Ono et al. 1990). One of the Kaempferol derivatives, Kaempferol 3-O-β-D glucopyranosides had little effect on protease enzyme but showed a significant reduction in gp120/CD4 interaction (Mahmood et al. 1996; Brinkworth et al. 1992).

Canthium coromandelicum (Burm.f.) Alston

Canthium coromandelicum is commonly known as Carray cheddie. This is the plant of Rubiaceae family. It is cultivated in Maharashtra, Tamil Nadu, Andhra Pradesh, Karnataka and Kerala. Leaf extract of C. coromandelicum showed HIV-1 reverse transcriptase inhibition and gp120 binding inhibition. Methanolic leaf extract of this plant reported to inhibit HIV-RT and gp120 binding with 78.67% and 72.52% inhibition (Chinnaiyan et al. 2013). Quercetin, Kaempferol and Astragalin are effective phytoconstituents of methanolic leaf extract with anti-HIV activity (Patro and Sasmal 2015).

Oldenlandia diffusa (Willd.) Roxb.

Oldenlandia diffusa belongs to family Rubiaceae. In Assam, it is known as Bon-jaluk. It is used in Folk medicine and Traditional Chinese medicine. It is cultivated in tropical and subtropical region of India. Aqueous extract of this plant showed more than 80% inhibition against HIV-PR at 250 µg/ml. This plant is reported to elicit moderate inhibition of HIV-IN enzyme. Chemical constituents of the whole plant extract of O. duffusa are Quercetin, kaempferol, scopoletin, 2-hydroxy-3-methylanthraquinone, 2-hydroxy-l-methoxyanthraquinone, α-linolenic acid, vanillic acid, p-hydroxyphenylethanol and, β-sitosterol. Majorly, Quercetin and kaempferol showed anti-HIV activity among these phyoconstituents (Liang et al. 2008; Ganbold et al. 2010).

Eclipta prostrate (L.)

Eclipta prostrate L. is well known Indian medicinal plant of the family Asteraceae. It is also known as Bhringaraj. It is mainly cultivated in pantropical areas. In India, it is widely distributed in Uttrakhand. It is used in Ayurveda, Folk medicine, Siddha, and Traditional Chinese medicine. Whole plant parts are reported to exhibit anti-PR and anti-IN activity (Tewtrakul et al. 2007). 5-hydroxymethyl-(2,2′:5′,2″)- terthienyl tiglate, 5-hydroxymethyl-(2,2′:5′,2″)-terthienyl acetate and Ecliptal showed inhibition of HIV-PR with IC50 values 58 µM, 93 µM and 83 µM, respectively (Tewtrakul et al. 2007, 2006). Orobol and Wedelolactone showed HIV-PR inhibition with IC50 values of 8 µM and 4 µM, respectively (Tewtrakul et al. 2007; Han et al. 2015). List of phytoconstituents with multi-targeted activities are given in Table 6. Overall, a comprehensive list of all medicinal plants with their pharmacological activities are reported in Table 7.

Table 6 Chemical structures of phytoconstituents having multi-targeted inhibitory activity
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Table 7 A comprehensive list of pharmacological activities of tropical medicinal plants
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Critical assessment and discussion

Nature has always provided the cure for the treatment of many complicated diseases including HIV. Over the past decades, promising developments have been made in the investigation of medicinal plants as anti-HIV agents. These agents belong to various structurally diverse scaffolds like coumarins, terpenes, alkaloids, flavonoids, tannins, etc. Most of these scaffolds serve as leads for the development of novel anti-HIV agents. This section describes the future of phytoconstituents reviewed here. For this purpose, a pharmacophore modeling was carried out using 14 diversified and representative phytoconstituents having anti-HIV activity on different enzymes and receptors (reverse transcriptase, protease, integrase, cell fusion, CCR5 and CXCR4).

Pharmacophore is a combination of chemical structural features and their biological activities. Pharmacophore mapping has proved successful role in ligand and structure based drug design for the development of potent bioactive molecules. Pharmacophore modeling is used to find common chemical structural features responsible for biological activity like hydrophobic region, hydrogen bond donor, and hydrogen bond acceptor from the diversified chemical structures. In present work, Pharmacophore modeling was performed using SYBYL X 1.2 software. All the phytoconstituents were drawn by SKETCH module of SYBYL X 1.2. The chemical structures of molecules used for pharmacophore generation is given in Table 8. Partial atomic charges were calculated by the Gasteiger Huckel method. A Tripos force field was used with a distance-dependent dielectric and the Powell conjugate gradient algorithm conjunction criterion of 0.01 kcal/mol Å during the process of energy minimization. A total number of 10 models were generated for each hypothesis using DISCOtech. The best model generated for each hypothesis by DISCOtech was again selected for refinement by Genetic algorithm similarity program (GASP). GASP is based on the genetic algorithm to characterize common features of different molecules from which hypothesis is generated. The objective of this step is to produce 3D query through proper alignment, to flatten out rings so that spatial query can be created for its use in substructure searching. By carrying out a GASP alignment, it is guaranteed that conformations which are used as input will look at least once in optimization. During this optimization, only stable and least energy conformer were retained and propagated to the next iteration of the genetic algorithm. All parameters were kept as default other than population size (125), mutation weight (96), fitness increment (0.02) and number of alignment (10).

Table 8 Chemical structures of phytoconstituents used for pharmacophore model generation
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After following the above mentioned procedure, A 3D Pharmacophore query was generated consisting of 4 features including donor site, donor atom, acceptor atom and hydrophobic region as depicted in Fig. 2a. For better understating of inter feature geometric distance responsible for interaction with biological target, a 2D pharmacophore model is also shown in Fig. 2b. (Bhatt et al. 2014b; Patel and Bhatt 2021).

Fig. 2
figure 2

Pharmacophore generated from anti-HIV Phytoconstituents a 3D representation of Pharmacophore b 2D representation of Pharmacophore

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These 4 features generated from pharmacophore can be used to design and discover potent and bioactive anti-HIV molecules. Based on the generated pharmacophore, structural requirements for anti-HIV activity is highlighted in Fig. 3.

Fig. 3
figure 3

Outcome of Pharmacophore modeling

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Presence of hydrophobic ring like phenyl and fusion of phenyl ring with heterocyclic rings (for example chromane ring) are essential for the anti-HIV activity. These ring systems are beneficial for multi target activities on different HIV enzymes. Substitutions on the phenyl ring with H-bond donor atoms like oxygen and nitrogen are critical for inhibition of HIV Protease, Integrase and cell fusion. Moreover, phenyl ring can be substituted with H-bond donor groups like –OH, -NH2 and –COOH for specific inhibition of Protease enzyme. Substitutions on heterocyclic ring with H-bond acceptor atoms and acceptor functional groups like –C = O and –OCH3 impart Reverse transcriptase, Integrase, CCR5 and CXCR4 inhibitory activities. Overall, the present study may facilitate the development of future leads from bioactive natural products for the treatment of HIV.

Conclusion

Acquired Immune Deficiency Syndrome (AIDS) is one of the leading causes of death worldwide. Current treatment available for HIV/AIDS have certain limitations like severe side effects and drug resistance so, there is an urgent need for safe, effective and functional treatment for HIV. Tropical countries are endowed with a rich source of medicinal plants with encouraging therapeutic activities. This review provides an insight about the medicinal plants having anti-HIV properties. Medicinal plants are classified as Reverse transcriptase (RT) inhibitors, Protease (PR) inhibitors, Integrase (IN) inhibitors, cell fusion inhibitors, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) inhibitors and muti-target inhibitors. Further, phytoconstituents present in an individual plant with their anti-HIV potencies are elaborated. Pharmacophore modeling was performed using these phytoconstituents for generation of potent leads for future development of anti-HIV drugs. This review may become helpful in identifying new treatment strategy using natural source for the treatment of HIV.