Bangladesh Journal of Pharmacology Mini-review BJP Introduction The utilization of medicinal plants is the subject of countless studies in the search for safe and efficient medical treatments for ailments. Plant-derived medi- cines have been utilised widely to treat a wide range of illnesses in the traditional medical systems of antiquity, including Ayurveda, Chinese, Egyptian, etc. Particu- larly secondary metabolites including alkaloids, glyco- sides, terpenoids, tannins, resins, etc. have been known to have a variety of therapeutic qualities, and plants have long been thought of as the source of chemicals. Research into ethnobotanical applications of the plants led to the discovery of 74% of pharmacologically active plant-derived components. It is estimated that 14-28% of higher plant species are used medicinally (Singh et al., 2016). An under shrub or herb, Barleria lupulina Lindl. (Acan- thaceae), is also referred to as kanta vishellakarani or shurma in Bengali (Suba et al., 2002; Shedange and Ya- dav, 1997), cem mulli or mullukanagaambaram in Tamil (Shedange and Yadav, 1997), landik in Indone- sian language (Suba et al., 2002) and in Thailand as slaed pang paw (Suksamrarn, 1986). In English it is been called as hop-headed barleria. The large, well- known, and pantropical genus Barleria contains more than 300 species of herbs and shrubs. Asia and Africa are the primary habitats for Barleria species. In India, there are between 26 and 32 species, one subspecies, and one variant B. prionitis Linn., B. noctiflora Nees., B. cristata Linn., B. montana Linn., B. grandiflora Dalz., B. lupulina Lindl., and B. strigosa Wild are among the principal medicinal species of the genus Barleria (Balk- will and Balkwill, 1997; Balkwill and Balkwill, 1998; Shedange and Yadav, 1997; Makholela et al., 2003). Recently reviews on this plant have been published (Lekhak et al., 2022; Sawarkar et al., 2022). Materials and Methods The relevant literature databases including Science Direct, PubMed, Research Gate, and Google Scholar were searched up to March 31, 2023. The publications were searched for using the keywords "Barleria lupu- lina," "Barleria lupulina and Pharmacology," and "Barleria lupulina and Phytochemistry". As a result we found articles for each key word. The databases' similar arti- cles were first filtered out. The studies that had nothing Abstract A well-known herb Barleria lupulina is traditionally used as a medicinal and decorative plant. The various parts of this plant are reported to contain a range of phytoconstituents, including terpenes and terpenoidal compounds, iridoid glucosides, iridoid diglucosides, phenylpropanoid glucosides, and phenylethanoid glucosides. Antibacterial, antiarthritic, CNS depressive, anti- osteoporotic, antioxidant, anti-diabetic, and anti-inflammatory effects are present in isolated components and extract of B. lupulina. This in-depth analysis covers the traditional uses, phytochemistry, pharmacological use, and mechanism of action of B. lupulina. Article Info Received: 4 July 2023 Accepted: 12 December 2023 Available Online: 17 December 2023 DOI: 10.3329/bjp.v18i4.47429 Cite this article: Sawarkar HA, Pandey AK, Biyani KR. Phytochemicals and therapeutic po- tentials of Barleria lupulina. Bangla- desh J Pharmacol. 2023; 18: 119-129. Phytochemicals and therapeutic potentials of Barleria lupulina Hemant A. Sawarkar1, Ajit Kumar Pandey2 and Kailas R. Biyani1 1Department of Pharmacognosy and Phytochemistry, Anuradha College of Pharmacy, Chikhli, Buldhana, Maharashtra 443201, India; 2Department of Pharmaceutical Chemistry, Shri Shankaracharya Technical Campus, Faculty of Pharmaceutical Sciences, Junwani, Bhilai, Chattisgarh 490020, India. This work is licensed under a Creative Commons Attribution 4.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2023; 18: 119-129 Journal homepage: www.banglajol.info; www.bdpsjournal.org Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Global Health, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088 to do with phytochemistry, biological activities, or pharmacology were subsequently eliminated. Patents, abstracts, case studies, and abstracts from congresses and symposiums were removed because they lacked adequate details. Following the exclusion criteria, 44 articles (34 research articles, 6 reference articles, and 4 irrelevant articles) were discovered to be pertinent to B. lupulina. Finally, two pieces that discussed its agricultu- ral pursuits were excluded from the inclusion require- ments. The phytochemical profile of B. lupulina was discovered to be similar to that of B. prionitis, thus some articles were added to explain the mechanism and ac- tive ingredients behind the pharmacological effects of B. lupulina. Uses in Traditional Medicines Traditionally, the whole plant or leaf was used in different diseases. They are either administered orally or applied locally. Inhabitants of rural Tamilnadu, India utilized the fresh juice of the crushed B. lupulina plant to relieve tension and mental strain (Suba et. al., 2002). Whereas the rural people in West Bengal, India used the plant's aerial portions to treat diabetes, snake bites, and rheumatoid arthritis (Chopra et al., 1968). In case of of snakebites, it was used topically. In addition to snakebites, the Thai people applied topically to treat as an anti-inflammatory against bug bites, herpes simplex, and varicella zoster virus lesions. The leaves of B. lupulina have long been used as a diure- tic and tonic as well as a remedy for swelling, indiges- tion, constipation, jaundice, wounds, scabies, and uri- nary infections (Kanchanapoom et al., 2001; Lans et al., 2001; Sawangjaroen et al., 2006; Elsai, 1995). In Thailand, the leaf paste was used as a poultice to treat pain and the leaf juice was given to stop bleeding after a cut. The plant had an anti-acne (Chomnawang et al. 2005) and antiamoebic effect. Phytochemistry Phytochemicals like iridoids, iridoid glucosides and glycoside, phenylpropanodanoid glycosides, etc were isolated from the different extracts of the plant. Phyto- chemicals like barlerin, acetyl barlerin, shanziside and different shanziside derivatives, ipolamiidoside, ipola- miide, saletpangponosides, phlororigodoside, mussae- noside, mussanosidic acid and barlupulins can be classified as iridoid glycosides and iridoid glucosides. Phytochemicals like, lupulinoside, poliumoside, deca- ffeoyl acteoside etc. can be included in the category of iridoid di-glycosides. Protocatechonic acid -4-O-β-glu- coside, vanillic acid -4-O-β-glucoside, leonuriside may be categorized as phenolic glycosides. Compounds such as forsythoside B, verbascoside (phenyl propanoid gly- cosides); (+)-lyoniresinol 3α-O-glycopyranoside (lignan glycosides); (3R)-1-octan-3yl-β-primeveroside (aliphatic glycoside) and benzyl alcohol β-(2’-O-β-xylopyranosyl) glucopyranoside (benzyl alcohol glycoside) also been reported (Kim et al., 2016). Also, two novel 4,8,8-tri- methyl cyclooct-2-enone derivatives chkyunglupulins A and B were isolated. 4-ethyl catechols, 4-methyl cate- chols and 4-vinyl catechol were tannins isolated from hot aqueous extract from aerial parts of B. lupulina (Senger et al., 2016). Thus, B. lupulina plant as such can be termed to be containing abundance of glycosidal constituents. However, the natures of aglycones were found to be iridoid, phenylpropanoid and phenolic. The only study conducted on essential oil reported presence of cyclobutane, 1,1-dimethyl-2-octyl, 2-hexyl-1-octanol, 1, 2-benzenedicarboxylic acid, mono(2-ethylhexyl) ester and 1-hentetracontanol as components of essential oil may be termed as terpenoids. Table I discusses most abundant phytochemicals like iridoid, phenylethanoid glycosides, tannins and com- ponents of essential oil of B. lupulina along with isola- tion processes for the phytochemicals and methods used for identifying phytochemicals. Iridoid glucosides were discovered for the first time in the aerial sections of B. lupulina (Suksamrarn et al., 1986). Authors reported about the use of 95% ethanol as a solvent for the extraction. Further, after concentrating the aqueous ethanolic extract and washings with hexane, the lower phase was chromatographed on a silica gel column using methylene chloride, methanol as eluent. Methylene chloride : methanol (90 : 10 and 80 : 20) reported to be containing acetyl barlerin, barlerin and shanzhiside methyl ester. Physical (melting points of acetates) and spectroscopic comparisons UV, IR, 1H and 13C NMR) were compared with reported data to reveal the identities of these compounds. In an effort to correlate the pharmacological properties of the recognized compounds from B. lupulina, authors reported the anti HSV-1 activity of compound [5] with an IC50 value of 41.1 µg/mL. The only other discovered molecule with a C5-hydroxyl group is compound [5], indicating that the presence of this group is required for anti-HSV-1 activity (Suksamrarn et al., 2003). Iridoid compounds [1–10, 17 and 19] and four new compounds [24–27] had no discernible effect on the growth of the stat 3 activated cancer cell lines MDA-MB -231 (breast cancer) and U-251MG (glioblastoma), which are both breast cancer and glioblastoma, respec- tively. Additionally, scientists discovered that chemi- cals [10] and [19] only had weak free radical scavenging action, with an IC50 of only 100 g/mL (Kim et al., 2015a). Two novel compounds (chakyunglupulin A [29] and chakyunglupulin B [30]), along with six previously found substances, were tested for cytotoxicity and anti- bacterial activity. None of the compounds were appa- 120 Bangladesh J Pharmacol 2023; 18: 119-129 rently found to be cytotoxic and active against the examined bacteria (Kim et al., 2015b). The presence of cyclobutane, 1,1-dimethyl- 2-octyl, 2-hexyl-1-octanol, 1, 2-benzenedicarboxylic acid, mono(2-ethylhexyl) ester, and 1-hentetracontanol added to the essential oil's anti- bacterial activity against Bacillus pumilus and Staphylo- coccus aureus (Sarmad et al., 2012). Thirteen iridoid glycosides were identified from a 70% ethanolic extract of B. lupulina. Using the activity of the enzyme alkaline phosphatase as a marker, the impact of the separated chemicals on the differentiation of the MC3T3-E1 cells was examined. With the exception of compound [5] all substances raised the alkaline phosphatase activity in a dose-dependent manner and at varying intensities Among the compounds tested, ipolamiide [14] showed the strongest stimulatory effect followed by acetyl bar- lerin [3] and 6-O-acetylshanzhiside [23] ( Widyowati et al., 2010). Tables II describes the parent chemical structure and describes some of the chemical constituents isolated from B. lupulina relating to the parent structure A respectively. The parent structure A with 1H NMR data are presented. While going through various research papers available relating to the phytochemistry of B. lupulina, it was noticed that majority of the compounds isolated from the B. lupulina were found to belong to parent structure A category of compounds called as iridoid glucosides. Apart from iridoid glucosides, phenyl ethanoid glycosides are reported to be present in B. lupulina. Essential oil as usual was found to be containing various terpenoidal compounds. Terpenoi- dal compounds such as 1,H-3a methanoazulene, 3,7,- 11,15, tetramethyl-2-hexadecanoic acid, benzene, cis- thiosphene, oxyranehexadcyl (phytol), phytol acetate and ethyl 9,12,15-octadecatrienoate were reported in extracts from the leaves of B. lupulina (Kumari and Dubey, 2016a). Compounds such as forsythoside B, verbascoside (phenylpropanoid glycosides); (+)-lyoni- resinol 3α-O-glycopyranoside (lignan glycosides); (3R)- 1-octan-3yl-β-primeveroside (aliphatic glycoside) and benzyl alcohol β-(2’-O-β-xylopyranosyl) glucopyrano- side (benzyl alcohol glycoside) also been reported (Kim et al., 2016). Flavones 2(4H)-benzofuranone, benzofura- none and phenolics like benzyl benzoate, methyl para- ben were also been reported in acetone and methanol extracts of leaves of B. lupulina (Kumari and Dubey, 2016b). Therapeutic Potentials Antimicrobial activity Extracts from B. lupulina were effective against HSV-2 (Herpes Simplex virus type-2). One of nine iridoid glycosides obtained from the plant's flower extracts that exhibited anti-HSV action was ipolamiidoside [5] (Yoo- sook et al., 1999; Kanchanapoom et al., 2001; Susksa- mrarn et al., 2003). In order to determine the antimicrobial effects of among 19 Thai medicinal plants against acne causing micro- organism, B. lupulina, along with other three medicinal plants which showed the highest zone of inhibition (Chomnawang et al., 2005). It was proven from different studies that, B. lupulina leaf methanol extract had antibacterial potential and produced zones of inhibition against B. pumilus, S. aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus mutans and Salmonella enteri- tidis (Doss et al., 2011; Moin et al., 2012; Dey et al., 2014). The plant's fresh extract had a 16.5% concentration of antibacterial activity (Pattanayal et al., 2014). In a different investigation, it was discovered that the antibacterial properties of acetone, methanol, and water -soluble extracts of B. lupulina's leaf and stem were effective against S. typhi, E. coli, P. aeruginosa, K. pneu- moniae, and S. aureus. Acetone-soluble leaf and stem extracts induced the largest zone of inhibition for P. aeruginosa, and methanol-soluble leaf and stem extracts for S. typhi. But K. pneumoniae was suppressed by every extract. B. lupulina leaves' ethanol and aqueous extracts demonstrated antibacterial effectiveness in a different investigation against E. coli, P. aeruginosa, S. aureus, S. typhi, and K. pneumoniae (Kumari and Dubey, 2016a, 2016b, and Kumari and Dubey, 2017). B. pumilis and S. aureus were shown to be effectively inhibited by essential oil from B. lupulina leaves. Furthermore, accor- ding to Sarmad et al. (2012), the presence of at least 15 components is what gives essential oils their antibac- terial properties. CNS depressant activity One study examined the effects of a methanol extract of B. lupulina's aerial parts on CNS activity. For this, expe- rimental models involving Swiss albino mice and Wistar rats were used. The methanol extract (100, 200, and 300 mg/kg) lowered the overall behavioral pattern (spontaneous activity, alertness, awareness, pain res- ponse, and touch reaction) in a dose-dependent man- ner. The extract considerably decreased the exploratory behavioral profile (Y-maze test and head dip test) and conditioned avoidance response with each of the tested doses. The methanol extract showed excellent motor in- coordination and muscle-relaxing abilities. The extract also prolonged the phenobarbitone sodium-induced sleep time (Suba et al., 2002). Anti-diabetic activity The anti-diabetic study was evaluated for methanol extract of aerial portions of B. lupulina in streptozotocin- induced male Wistar rats. In comparison to the control group, a methanol extract of the aerial portions of B. lupulina significantly reduced blood sugar levels at all levels evaluated 4 hours after administration, and the Bangladesh J Pharmacol 2023; 18: 119-129 121 effect remained for up to 12 hours. The extract's maxi- mal effect was visible after 12 hours at doses of 200 mg/kg of body weight and higher. The group given 300 mg/kg body weight showed the most significant activity (15.4% blood glucose reduction) after 12 hours after administration, whereas the conventional medica- tion, glibenclamide (10 mg/kg body weight), showed a blood glucose reduction of 18.8% at the same time interval (Suba et al., 2004). Identification of 4-ethyl catechols, 4-vinyl catechols in hot aqueous extract of an herbal medicine of B. lupulina and fermented noni (Morinda citrofolia) as cofactors to activate Nrf2, an important pathway to be activated for potential diabetic wound healing activity in a cell line study (Senger and Cao, 2016). Anti-inflammatory activity Carrageenan-induced rat paw edema and ethyl phenyl- propiolate induced ear edema models were used to assess the ex vivo anti-inflammatory properties of methanolic extract of B. lupulina. The herb was disco- vered to have a significant inhibitory effect against edema swelling in live animal models (Wanikiat et al., 2008). Additionally, authors investigated the effect of B. lupulina on neutrophil migration and found that it significantly decreased neutrophil chemokinesis and chemotaxis. The plants significantly reduced the release of myeloperoxidase and elastase, according to this study's findings (Wanikiat et al., 2008). Similar to this, B. lupulina aerial part methanol extract anti-inflamma- tory activity had been reported, displaying significant inhibition of carrageenan and serotonin-induced rat paw edema volumes in comparison to the untreated group. Methanol extract significantly decreased granu- loma weight in a cotton pellet-induced granuloma model (Suba et al., 2005). Additionally, there are reports about the Nrf2 defense mechanism, which protects against inflammatory damage, was activated by B. lupulina hot aqueous extract of aerial parts. Numerous catechols (4-ethyl catechols, 4-methyl catechols, 4-vinyl catechol) identified by LC-MS were found responsible for activating the Nrf2 pathway, were also discovered as a result of this investigation. The results were deter- mined using cell line studies on human dermal micro- vasular endothelial cells. (Senger et al., 2016). The aque- ous fraction of whole plant hydromethanolic extract of B. prionitis whole plant have shown significant anti- inflammatory activity in the acute inflammation indu- ced by carageenan, histamine and dextran in rats (Singh et al., 2003). Authors reported the anti infla- mmatory activity may be due to presence of iridoid glucoside, shanziside methyl ester, acetyl barlerin and barlerin. Antiarthritic activity The antiarthritic activity of methanol extract of B. lupu- lina leaves at 300 and 600 mg/kg body weight was examined in models of arthritis produced by formalin, adjuvants, collagen type II, and monosodium iodo- acetate using Wistar rats. During the research period, extracts at doses of 300 mg/kg and 600 mg/kg signi- ficantly prevented the development of edema and myeloperoxidase activity while significantly restoring antioxidant activity. At 300 mg/kg and 600 mg/kg, methanol extracts significantly increased levels of hemoglobin, serum albumin, total protein, calcium, and phosphorus, while significantly lowering levels of leu- cocyte count and erythrocyte sedimentation rate were observed (Mazumder et al., 2012). Anti-osteoporotic activity Using alkaline phosphatase activity in MC3T3-E1 oste- oblast cells as a marker, 32 Indonesian medicinal herbs were examined for their effects on osteoblast development. The 70% ethanol extract of the aerial portions of B. lupulina was found to have the strongest alkaline phosphatase-enhancing activity. Utilizing ALP activity as a marker, the effect of the separated chemi- cals on the differentiation of the MC3T3-E1 cells was examined. With the exception of [5], every com- pound raised the alkaline phosphatase activity, albeit to varying degrees and in a dose-dependent manner. Ipo- lamiide [14], acetyl barlerin [3] and 6-O-acetyl-shanzi- side [23], all had the greatest stimulatory effects among the substances examined (Widyowati et al., 2010). Immunomodulatory activity According to the findings of an immunomodulatory study conducted on a methanol extract of B. lupulina using rats, the immune system was improved by rai- sing blood leukocyte count, spleen weight, spleen leu- kocyte count, and paw volume on delayed type hyper- sensitivity footpad thickness (Mazumder et al., 2012). Anti-cataract activity The in vitro activity was carried out using by glucose- induced caractogenesis using goat lenses. When com- pared to the positive control group (glucose), the lenses incubated with ethyl acetate fraction of methanol extract of B. lupulina at 200 and 400 g/mL concentration seemed to slow the progression of lens opacification and showed a significant restoration of glutathione, superoxide dismutase level and reduced level of TBARS. With a lower IC50 value, ethyl acetate fraction of methanol extract demonstrated promising percen- tage inhibition of aldose reductase activity (Mazumder et al., 2014). Antiulcer activity The gastric cytoprotective properties of a methanol extract of the aerial parts of the plant B. lupulina were evaluated using a range of ulcer models, such as drug- induced ulcers, constraint ulcers, duodenal ulcers, and pylorus ligated ulcers. The extract at the tested dose of 200 mg/kg considerably reduced the amount of gastric juice, overall acidity, and the ulcer index in pylorus- 122 Bangladesh J Pharmacol 2023; 18: 119-129 ligated rats. Additionally, it offered crucial protection against ulceration brought on by alcohol, indomethacin, and stress. Additionally, rats given indomethacin had less TBARS (thiobarbituric acid reacting substances) in their stomachs when administered with the extract of the plant. In addition, it offered protection against duodenal ulcers (Suba et al., 2004). Antiamebic activity The antiamebic abilities of 12 Thai medicinal herbs were examined against Entamoeba histolytica strains HTH-56: MUTM and HM1: IMSS growing in vitro. These herbs are frequently utilized by AIDS patients in southern Thailand. The extracts from B. lupulina, Alpinia galanga, Boesenbergia pandurata, Piper betle, and P. chaba, as well as those from methanol extract B. pandurata, were classified as being active, whereas those from Murraya paniculata and Zingiber zerumbet were classified as being moderately active (Sawangjoroen et al., 2006). Antioxidant activity According to reports, shanziside methyl ester and shan- ziside have a negligible ability to scavenge DPPH (Kim et al., 2015a). The total phenolic content and DPPH free radical scavenging activity of B. lupulina's methanolic leaf and stem extracts were evaluated in a related study. The stem extract was found to have a higher phenolic content, but the leaf extract showed stronger free radical scavenging activity with an IC50 value of 48.9 (µg/mL) (Kumari et al., 2017). Eighty percent (v/v) ethanol at 400 W for 30 sec were shown to be the best conditions for extracting anti- oxidant compounds by microwave assisted extraction. Four new phenylethanoid glycoside chemicals (lavan- dulifolioside, cistanoside C, tubuloside B, and betonyo- side A) were successfully discovered in the species through analysis using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spec- trometry (Suhaimy et al., 2021). However, the role of antioxidant in the treatment of different diseases re- mains to draw any conclusion. Table I Phytochemicals reported in Barleria lupulina along with methodology for isolation and identification Part Compound References Isolation, identification method Aerial part Shanziside methyl ester [1]; 8-O-acetyl shanziside me- thyl ester (barlerin) [2]; 6, 8-O-O-diacetyl shanziside methhyl ester (acetyl barlerin) [3] Suksamrarn et al., 1986 Ethanolic extract: Column chro- matography; physical compari- son and spectroscopic (UV, IR, NMR) Aerial part 6-O-Acetyl shanziside methyl ester [4], ipolamiidoside [5] Byrne et al., 1987 Column chromatography; 1H and 13C NMR, MS and X-ray diffrac- tion Aerial part Shanziside methyl ester [1]; 8-O-acetyl shanziside me- thyl ester (barlerin) [2]; 6, 8-O-O-diacetyl shanziside methyl ester (acetyl barlerin)[3], 6-O-acetyl shanziside methyl ester [4], ipolamiidoside[5], 6-O-p-methoxy-cis- cinnamoyl 8-o-acetyl shanziside methyl ester [6]; ; 6-O-p -methoxy-trans-cinnamoyl 8-O-acetyl shanziside me- thyl ester [7]; ; 6-O-p-methoxy-cis-coumaroyl 8-O-acetyl shanziside methyl ester [8]; ; 6-O-p-methoxy-trans- coumaroyl 8-O-acetyl shanziside methyl ester [9] Tuntiwa- chuwuttikul et al., 1998 Column chromatography fol- lowed by re-chromatography and RHPLC;UV, IR, 1H and 13C NMR, HRFAB-MS and comparative study for known compounds Aerial part Ipolamiidoside [5], 8-O-acetyl-6-O-trans-p-coumaroyl shanziside [10]; saletpangponoside A [11], sal- etpangponoside B [12]; saletpangponoside C [13], ipola- miide[14]; phlororigidosideB [15]; 8-O-acetyl mussaeno- side [16] Kanchanapoom et al., 2001 Column chromatography fol- lowed by HPLC-ODS; 1H and 13C NMR, HRFAB-MS and compara- tive study for known compounds Flower Shanziside methyl ester [1], 8-O-acetyl shanziside me- thyl ester [2], 6, 8-O-O-diacetyl shanziside methyl ester (acetyl barlerin) [3], 6-O-acetyl shanziside methyl ester [4], ipolamiidoside [5], musaenosidic acid [17]; 8-O- acetyl shanziside [18], shanziside [19] Suksamrarn et al., 2003 Column chromatography fol- lowed; 1H and 13C NMR, HRFAB- MS and comparative study for known compounds Determination of structure of new compound by 2D-NMR Widyowati et al., 2010 Extraction followed by fractiona- tion with polar solvents followed by reversed phase MPLC and pTLC; 13C NMR, HRFAB-MS and comparative study for known compounds Bangladesh J Pharmacol 2023; 18: 119-129 123 Anticlastogenic activity The chromosome protective ability of aqueous leaf extract of B. lupulina was assessed in mice (Sur and Das 131). They split up animals into three groups: pre and post treatment sets I and III respectively. Set II was maintained as control (the mice's whole body was exposed to cobalt (Co-60) 1.2 Gy of γ-irradiation. Set I mice received injections of 1 mL of an aqueous extract per 100 g of body weight, and one hour later, the entire body was subjected to 1.2 Gy of γ-irradiation from cobalt (Co-60). Set III involved the exposure of mice to γ -irradiation (1.2 Gy) from cobalt (Co-60), and following a one-hour injection 1 mL of an aqueous extract per 100 g of body weight. The study of aberration was conduc- ted at 1, 16, 48 hours, 1 and four weeks for every group of animals. There was an increase in aberration in the control (set II) from the initial to 48 hours (16.6%). Similarly, for same for interval, sets I and III had shown aberrations of 7.5% and 4.6%, respectively. Correspon- dingly. For the set III, the percentage aberration was modest. Comparing set III mice (0.2% with transloca- tion) to set I using chromosomal dissociation, (0.3%) and control set II (1.9 with chromosome dislocation, 1.9% with chromatid beak). The outcomes revealed the aqueous extract of B. lupulina played a major part in radiation protection against structural chromosomal damage caused by γ-rays harm in mice. Antitumor activity The leaf extract of B. lupulina possesses the ability to fully decrease the tumor (ulcer proliferative growth) that was caused by γ-rays (1.2 Gy) that happened near the nostril in fresh water Oreochromis mossambicus tilapia fish in nine days (Sur and Dass, 2012). Structure Activity Relationship Iridoids belong to the large family of terpene deriva- tives. Iridoid glycosides are produced from cyclopeta- noid monoterpenes with eight, nine, or 10 carbons (Boros and Stermitz, 1990). These compounds have a bicyclic cyclopentanoyran ring system, which suggests that the cyclopentane ring serves as the primary ring system in these compounds. Seco iridoids are produced Table I Phytochemicals reported in Barleria lupulina along with methodology for isolation and identification (Cont.) Part Compound References Isolation, identification method Essential oil Cyclobutane,1,1-dimethyl-2-octyl, 2-hexyl-1-octanol, 1, 2-benzenedicarboxylic acid, mono(2-ethylhexyl) ester, 1 -hentetracontanol Sarmad et al., 2012 GC-MS Aerial part Shanziside methyl ester [1]; 8-O-acetyl shanziside me- thyl ester (barlerin) [2]; 6, 8-O-O-diacetyl shanziside methyl ester (acetyl barlerin) [3], 6-O-acetyl shanziside methyl ester [4], ipolamiidoside [5], 6-O-p-methoxy-cis- cinnamoyl 8-O-acetyl shanziside methyl ester [6]; ; 6-O- p-methoxy-trans-cinnamoyl 8-O-acetyl shanziside me- thyl ester [7]; 6-O-p-methoxy-cis-coumaroyl 8-O-acetyl shanziside methyl ester [8]; 6-O-p-methoxy-trans- coumaroyl 8-O-acetyl shanziside methyl ester [9], 8-O- acetyl-6-O-trans-p-comaroyl shanziside [10], musaeno- sidic acid [17], shanziside [19]; barlupulin A [24], barlu- pulin B [25]; barlupulin C [26], barlupulin D [27], lu- pulinoside [28] Kim et al., 2015a Ethyl acetate soluble fraction of aqueous extracts followed by preparative HPLC; LC-MS of extract, 1H and 13C NMR, HRESI- MS, IR and comparative study for known compounds Aerial part Chakyunglupulin A [29]; chakyunglupulin B [30] Kim et al., 2015b Ethyl acetate soluble fraction of aqueous extracts followed by preparative HPLC; LC-MS of extract, 1H and 13C NMR, HRESI- MS, IR and comparative study for known compounds Aerial part Poliumoside [31]; dacaffeoyl acetoside [32], protocate- chuic acid 4-O-β-glucoside[33]; vanillic acid 4-O-β- glucoside [34], Leonuriside [35], forsythoside B [36], verbascoside [37] Kim et al., 2016 Ethyl acetate soluble fraction of aqueous extracts followed by preparative HPLC; LC-MS of extract, 1H and 13C NMR, HRESI- MS, IR and comparative study for known compounds Aerial part 4-Ethyl catechols, 4-methyl catechols, 4-vinyl catechol Senger et al., 2016 Hot aqueous extract; LC-MS Leaf Lavandulifolioside, cistanoside C, tubuloside B, betony- oside A Suhaimy et al., 2021 Microwave assisted extraction with ethanol (varying concentra- tion); UHPLC-QTOF/MS 124 Bangladesh J Pharmacol 2023; 18: 119-129 Table II Iridoids from Barleria lupulina Structure A Compound No. Compounds (Structure A) R R1 R2 R3 R4 1 Shanziside methyl ester H H H Me OH 2 8-O-Acetyl shanziside methyl ester (barlerin) H H Ac Me OH 3 6,8-O-O-Diacetyl shanziside methyl ester (acetyl barlerin) H Ac Ac Me OH 4 6-O-Acetyl shanziside methyl ester H Ac H Me OH 5 Ipolamiidoside OH H Ac Me OH 6 6-O-p-Methoxy cis-cinnamoyl 8-O-acetyl shan- ziside methyl ester H p-Methoxy cis- cinnamoyl Ac Me OH 7 6-O-p-Methoxy trans-cinnamoyl 8-O-acetyl shan- ziside methyl ester H p-Methoxy trans- cinnamoyl Ac Me OH 8 6-O-p- cis-Coumaroyl 8-O-acetyl shanziside me- thyl ester H p-cis-Coumaroyl Ac Me OH 9 6-O-p-Trans-coumaroyl 8-O-acetyl shanziside methyl ester H p-trans-Coumaroyl Ac Me OH 10 8-O-Acetyl 6-O trans-p-coumaroyl shanziside H trans-p-Coumaroyl Ac H OH 11 Saletpangponoside A (6-O- (4’-O-β-glucopyrano- syl)-trans-p-coumaroyl-8-O-acetylshanzhisi- demethyl ester) H (4’’’-O-β-Glucopyra- nosyl)-trans-p- coumaroyl- Ac H OH 12 Saletpangponoside B(6-O- (4’-O-β-glucopyrano- syl)-cis-p-coumaroyl-8-O-acetylshanzhiside me- thyl ester) H (4’-O-β-Glucopyra- nosyl)-cis-p- coumaroyl O-Glc Ac Me OH 13 Saletpangponoside C (8-O-p-dihydrocoumaroyl shanzhiside methyl ester) H H trans-p- coumaroyl Me OH 14 Ipoliimide OH H H Me OH 15 Phlorigidoside B OH OH Ac Me OH 16 8-O-Acetyl mussaenoside OH H Ac Me OH 17 Musaenosidic acid H H H H OH 18 8-O-Acetyl shanziside H H Ac H OH 19 Shanziside H H H H OH 20 8-O-Acetylipolamiidic acid OH H Ac H OH 21 8-O-Acetyl-6-O-(p-methoxy-cis-cinnamoyl) shanzhiside H p-Methoxy-cis- cinnamoyl Ac H OH 22 8-O-Acetyl-6-O-(p-methoxy-transcinnamoyl) shanzhiside H p-Methoxy trans- cinnamoyl Ac H OH 23 6-O-Acetylshanzhiside H Ac H Me OH 24 Barlupulin A H OH Ac Me COOH 25 Barlupulin B H OAc Ac Me COOH 26 Barlupulin C H OH H H COOH 27 Barlupulin D H COOH H H OH O OR3O R R1 O O R2O R4H2C HO OH OH Me Bangladesh J Pharmacol 2023; 18: 119-129 125 when the cyclopentane ring is broken, while iridoid derivatives are produced when the pyran ring is bro- ken. Many ancient medicinal plants contain iridoids, which are used as bitter tonics, sedatives, antipyretics, cough syrups, wound healers, hypotensives, and reme- dies for skin ailments. These substances showed hepa- toprotective, purgative, hypolipidemic, hypoglycemic, anti-inflammatory, antispasmodic, anti-cancer, antivi- ral, and antitumor properties (Dinda et al., 2007a). We closely looked the chemical structures of all the iridoids isolated from B. lupulina and enlisted them as per the chemical structures A (Table II, Supplementary Figure 1). B. lupulina crude extracts have antiviral efficacy against HSV-2 (Yoosook et al., 1999). Nine iridoid glycosides were identified from plant's floral extracts, but only one, ipolamiidoside [5], showed anti-HSV action (Susk- samrarn et al., 2003). The C5 -OH moiety on the parent structure may be the cause of the anti-HSV action. According to the aforementioned results, positions R1, R2, R3, and R4 may display the pharmacological effects of the phytochemicals and consequently the plant ex- tracts when substituted with various chemical groups. Shanziside methyl ester [1], 8-O-acetyl shanziside methyl ester (barlerin) [2], 6, 8-O-O-diacetyl shanziside methyl ester (acetyl barlerin) [3]; 6-O-acetyl shanziside methyl ester [4], ipolamiidoside [5]; 6-O-p-methoxy-cis- cinnamoyl 8-O-acetyl shanziside methyl ester [6]; ; 6-O- p-methoxy-trans-cinnamoyl-8-O-acetyl shanziside me- thyl ester [7], ipolamiide [14], 8-O-acetylshanzhiside [18], shanziside [19], 8-O-acetylipolamiidic acid [20], 8- O-acetyl-6-O-(p-methoxy-cis-cinnamoyl) shanziside [21], 8-O-acetyl-6-O-(p-methoxy-trans-cinnamoyl), shanziside [22] and 6-O-acetylshanzhiside [23] were reported alkaline phosphatase stimulatory activity except compound [5] (Widyowati et al., 2010). Ipolamiide [14] was found to be showing strongest of all the isolated compounds, bears acetyl group at R3, Table III Phytochemicals in Barleria lupulina along with pharmacological effect/mechanism of action References Phytochemical reported if any Pharmacological effect/Mechanism of action Chen et al., 1998 6-O-Trans-p-coumaroyl-8-O-acetyl shanziside methyl ester and its cis isomer Antiviral- Respiratory syncytial virus Amoo et al., 2009 Acetyl barlerin, barlerin, shanziside methyl ester, verbascoside, 6-O-acetylshanziside methyl ester Antifungal- fungi static and fungicidal- Zone of inhibition Singh et al., 2003 Shanziside methyl ester, barlerin, acetyl barlerin Acute anti-inflammatory Ata et al., 2009 Shanziside, 6-O-trans-p-coumaroyl-8-O-acetyl shanziside me- thyl ester, acetyl barlerin, barlerin Antioxidant activity- free radical scaveng- ing, Jaiswal et al., 2010 Acetyl barlerin, barlerin, shanziside methyl ester Anti-diarrhoeal- Reduction in gastrointes- tinal motility Ata et al., 2007, 2009; Amoo et al., 2011 Shanziside, 6-O-trans-p-coumaroyl-8-O-acetyl shanziside me- thyl ester, acetyl barlerin, barlerin, and 6-O-acetylshanziside methyl ester Enzyme Inhibitory- AchE inhibition Suksamrarn et al., 2003 Ipolamiidoside [5] Anti HSV-1 Sarmad et al., 2012 Cyclobutane,1,1-dimethyl- 2-octyl, 2-Hexyl-1-octanol, 1, 2- benzenedicarboxylic acid, mono(2-ethylhexyl) ester, 1- hentetracontanol Antimicrobial Widyowati et al., 2010 8-O-Acetylshanzhiside [18], shanzhiside [19], 8-O- acetylipolamiidic acid [20], 8-O-acetyl-6-O-(p-methoxy-cis cin- namoyl)shanziside [21], and 8-O-acetyl-6-O-(p-methoxy- transcinnamoyl), 6-O-acetylshanzhiside [23], also compounds [1 -4, 6, 7 and 14] Anti-osteoporotic (alkaline phosphatase enzyme enhancing) Senger et al.,2016 4-Ethyl catechols, 4-methyl catechols, 4-vinyl catechol In vitro anti-inflammatory; activation of Nrf2 pathway Amoo et al., 2009; Zhu et al., 2016; Alipieva et al., 2014 Verbascoside [36] Fungi static and fungicidal– zones of inhibition Central antifatigue, Neuroprotective, anti- inflammatory, antioxidant,anti- prolifrative, UV-protective against car- cinogenic effects Yang et al., 2020 Forsythoside B [37] Cardioprotective, anti-inflammatory, neuroprotective, lung protective, antibac- terial and anti-tumor 126 Bangladesh J Pharmacol 2023; 18: 119-129 would be the possible reason for its higher alkaline phosphatase stimulatory effects whereas ipolamiido- side [5] with no such group at R3 remains inactive for this particular therapeutic action. 6,8-O,O-diacetylshan- zhiside methyl ester (acetyl barlerin, [3]) the next active compound as reported by authors contains two acetyl group (at R2 and R3) and 8-O-acetyl shanzhiside [36], having acetyl group at R2 (structure A) would be possibly responsible for lower alkaline phosphatase sti- mulatory activity than ipolamiide. All other com- pounds although were found active in stimulating alka- line phosphatase activity contains acetyl group at some other positions. This would be a classical example of understanding SAR among the natural compounds of B. lupulina or thereby of other species of genus Barleria. B. prionitis is one of the extensively studied species of the genus Barleria, reported to have some identical phytoconstituents with diverse pharmacological actions as to that of B. lupulina. Bronchitis and cough are treated with an oral hot water extract of B. prionitis' dried leaves and roots (Krishnaraju et al., 2005; Ata et al., 2007). Infants who have RSV are more likely to experience fever and symptoms similar to asthma. A phenolic glycoside called verbascoside and three iridoid glycosides (barlerin, 6-O-trans-p-coumatroyl-8-O-acetyl -shanziside methyl ester, and 6-O-cis-p-coumatroyl-8-O- acetyl-shanziside methyl ester) were identified from B. prionitis. While barlerin was shown to be inactive, researchers reported the antiviral activity of a mixture (1:3) of the substances (6-O-trans-p-coumaroyl-8-O- acetyl-shanziside methyl ester and 6-O-cis-p-coumaroyl -8-O-acetyl shanziside methyl ester) against RSV (strain A2). Therefore, the coumaroyl moiety may be responsi- ble for the antiviral activity of the compounds (6-O- trans-p-coumaroyl-8-O-acetyl-shanziside methyl ester and 6-O-cis-P-coumaroyl-8-O-acetyl shanziside methyl ester) (Dinda et al., 2007b). Because barlerin, 6-O-trans-p -coumatroyl-8-O-acetyl-shanziside, and 6-O-cis-p-cou- maroyl-8-O-acetyl-shanziside methyl ester are also found in B. lupulina, it can be concluded that the coumaroyl moiety in structure A played a role in the antiviral effects of the plant. Cytogenetic Study Cytogenetic study on B. lupulina reveals tetrapoidal nature with chromosome number 2n = 40 (Devi and Mathew, 1991). 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