EXHAUSTIVE REVIEW ON THERAPEUTICAL ROLE OF SOME PHYTOCONSTITUENTS AND THEIR CHEMICAL ALTERATION

EXHAUSTIVE REVIEW ON THERAPEUTICAL ROLE OF SOME PHYTOCONSTITUENTS AND THEIR CHEMICAL ALTERATION

Shaifali Dubey *, Prabodh Shukla, Padmini Shukla and Shashi Alok

ESIC, Kanpur, Uttar Pradesh, India.

ABSTRACT: Introduction: Therapeutic agent must be compatible with its target. Their multiple interaction produces diversified therapeutic action. Chemical exploration of phytoconstituents unravels bio-interaction and strategic engineering of molecules generates wonderful leads in therapeutics. Method: The source of information has been accessed through multiple research and review article of peered journals. The logical mechanics has been putted to churn the spread about phyto therapeutics of natural and its semi-synthetic derivatives. Result: For developing and designing a receptor/target compatible structure, chemical diversity of plants provides very good source to have a potent and effective therapeutic agent. Study of natural chemical templates helps not only to understand bio-mechanism but also creates a different approach of treatment. This review targets different diseases with natural compounds with enlighting the semi-synthetic analogues study of some of them. Exploring the chemistry/various character of molecule may provide a better fit model with minimal or no side effect. Discussion: On the basis of data processed phytotherapeutics may be explored upfront in pharmaceutical industry. These phyto magical entities presenting the mechanism upto depth of protein, DNA and genetic moulding. In future there will be more research ground in this area producing novel and better alternative for treatment with minimal toxic effects.

Keywords: Receptor, Target, Natural chemical template, Semi-synthetic analogues

INTRODUCTION: We generally find many plants treating many diseases. So, these are main natural source which provide us the constituents compatible to our body structure. Structure of these plants derived compounds are a better fit model for different receptors.

As the chemistry of these compounds plays an important role so this review article states about the various plant derived constituents which are used in different diseases, and it throw some light on the development of semi-synthetic analogues of phyto-constituents.

The statistical data of each country shows the growth rate in consumption of herbal medicines due to their better desired therapeutic action and less side effects. Market of herbal medicines is raising and getting its place in economy chart. Herbal medicines cover their market in each continent weather Asian market or European. This raise was not noticed recently in previous decade but before that period. Like indicated in the pie chart stats of european market in late nineties ¹.

DIAGRAM 1: EUROPEAN HERBAL MEDICINE MARKET IN 1997 ($ BILLION)

FIG. 1: DATA ACCESS AND SELECTION

Specific Areas with Exhaustive use of Chemical Diversity in Plants:

Cardiovascular Disease: The diverse chemical nucleus are found in plants which are best suited for the activity in cases of heart disease such as digitalis which having steroidal nucleus. Digoxin inhibits sodium-potassium adenosine triphosphatase (Na⁺/K⁺ATPase) pump resulting into its positive inotropic effect ². The subsequent rise in intracellular Ca⁺⁺and Na⁺coupled with the loss of intracellular K⁺ increases contraction of muscles of heart. Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the atrioventricular (AV) node ³. The phytochemical compounds in tea and coffee with their metabolites modulates gene expression and effect the protective endogenous pathways. For the encountering cardiovascular disease the vascular tone is regulated by the effects on endothelial function, increased reverse cholesterol transport and inhibition of oxidative stress and platelet function ⁴.

Anti-diabetic: Diabetes mellitus is a complex disease where the type-2 diabetes (noninsulin-dependent) is prevalent. Although a good extent of research has been done in this area yet there is great demand for developing new anti-diabetic drugs ^{5, 6}. The side effects of synthetic drugs are the reason for developing new and better pharmaceuticals as alternatives ⁷. This turns the face towards natural sources such as the discovery and development of the biguanides ⁸. The insulin-like glucose transport stimulatory activity of tannic acid in 3T3-L1 adipocytes was reported where chemically synthesized 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucopyranose as well as its natural anomer α-PGG possess activity. It was found to affect the glucose transport, by inhibiting the insulin receptor. α-PGG phosphorylate insulin receptor and Akt, which causes activation of PI 3 -kinase and stimulates membrane translocation of GLUT-4 ⁹.

Anti-Hypertension: Phytochemicals explore the attractive target to develop anti-hypertensive drugs. There are many compounds which are having powerful anti-hypertensive action such as reserpine ¹⁰ which is a purified alkaloid of powerful hypotensive plant Rauwolfia serpentine and magnoflorine, aristolochic acid, aristoloside etc. found in Aristolochia manshuriensis. The thiocarbamate and isothiocyanate fractions of Moringaoleifera are used for treatment of hypertension ¹¹. Another plant in this category is P. harmala which biosynthesize harmine, harmaline, harmol and harmaloi owing the antihypertensive effects in anesthetized rats ¹². The flavanoid fraction of Astragalus complanatus was found to be effective in lowering blood pressurein both renal hypertensive rats and spontaneously hypertensive rats ^{13, 14}.

Anti-coagulant: Pulmonary emboli, deep vein thrombosis, strokes and heart attacks are associated with thrombolic disorders which can be fight better with anti-coagulants. Eichhornia crassipes (Pontederiaceae) contains flavonoids, alkaloids, terpenoids, steroids, anthraquinones & cardiac glycosides etc ¹⁵. But the polysaccharides present play their role against coagulation through the intrinsic pathway of the coagulation cascade. The other polysaccharide fraction from Poranavolubilis contains mainly galactose, galacturonic acid and mannose and causes thrombin inhibition that in turn is mediated by heparin cofactor II but not by antithrombin. The carboxyl group in galacturonic acid is significant in performing its anti-coagulant activity as when this group is reduced the activity disappears ¹⁶. The compounds found in aqueous and ethanol extract of Synclisia scabrida significantly (P<0.05) prolonged the prothrombin time of normal plasma, suggesting its anticoagulant properties ¹⁷.

Antioxidant Action: To fight against the injury in kidney due to oxidative stress phytochemicals act as antioxidant. In this process these reduce the lipid peroxidation and enhance the level of endogenous antioxidants ¹⁸. Plants are rich with the chemical library which response to cancer, mutagenesis, allergy and aging effect due to their antioxidant effect ¹⁹ such as resveratrol (3,5,4′-trihydroxy-trans-stilbene) in skin of grapes ²⁰. Phenolic acids (gallic, protocatechuic, caffeic, and rosmarinic acids), phenolic diterpenes (carnosol, rosmanol, and rosmadial), flavonoids (quercetin, and kaempferol), and volatile oils (eugenol, carvacrol and menthol) and some plant pigments (anthocyanin and anthocyanidin) having the same property ²¹. But here the antioxidant action is carried out by inhibiting enzymes to suppress free radical generation or chelating the trace elements or scavenging ROS. Some free radical generating enzymes are microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase, and NADH oxidase which are inhibited by flavonoinds. Epicatechin and rutin are strong radical scavengers and inhibitors of lipid peroxidation in-vitro. In flavonoid heterocycle the coplanarity free 3-hdroxyl play an important role for scavenging ability. The B ring is aligned with the heterocycle and A ring by formation of hydrogen bonds between B ring OH groups and 3-hydroxyl. The potent antioxidant activity of flavan- 3-ols and flavon-3-ols can be accounted for intramolecular hydrogen bonding in the 3’, 4’-catechol ²². For colchicin a study was carried out in parallel with anti-cancer agent 5-Flourouracil in ehrlich ascites carcinoma control mice. The result of study was indicative of antioxidant activity with a significant (P<0.01) decrease in tumor weight and a significant (P<0.01) improvement in biochemical parameters (insulin, alanine transaminase, aspartate transaminase, alkaline phosphatase, reduced glutathione, superoxide dismutase, glutathione peroxidase etc) ²³.

Hepato Protective Action: The ethanolic extracts of leaves of Melia azedarach Linn and Brassica oleracea L.var.capitata (300 mg/kg/p.o. and 500 mg/kg/p.o.) had shown potent hepatoprotective activity than Catharanthus Rosea in simvastatin induced hepatotoxicity in rats ^{24, 25}. Anthocyanin cyanidin-3-O-β-glucoside (C3G) increases hepatic Gclc expression which decreases hepatic ROS levels and proapoptotic signaling. It enhances phosphorylation of AMP response element binding protein to bind with DNA so that it can increase the Gclc transcription. Result of a study showed anthocyanin C3G was activating GSH synthesis through a novel antioxidant way against excessive ROS production and thus preventing the hyperglycemia-induced hepatic oxidative damage [26]. Silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease ²⁷. Silibinin, silydianine, and silychristine constitute a flavanoid found in Silybum marianum, Compositae ²². Silymarin causes cell proliferation to regenerate the by increasing biosynthesis of RNA, protein and DNA by stimulating DNA-dependent RNA polymerase 1 enzyme.

It mediates its action through inhibition of leukotriene, ROS scavenging, suppression of NF-κB activity etc ²⁸. The ethanolic extract of Mirabilis Jalapa Linn leaves in dose of 250 mg/kg and 500 mg/kg with anti-tubercular drugs significantly reduced liver biomarker enzymes. Different antioxidant parameters were suppressed and increased TBARs levels in anti-tubercular drugs administration ²⁹.

Anti-inflammatory Action: Several natural products act as anti-inflammatory agents such as curcumin, parthenolide, 1,8-cineole, pseudopterosins, bromelain ³⁰ and volatile oils obtained from lemon grass (Cymbopogoncitratus Stapf) ³¹. Verbascum mallophorums contains diverse polysaccharides, iroid glycosides and phenylentanoids. Verbascoside down regulate the activity of iNOS which follow the signal to produce nitric oxide using L-arginine as a substrate in response to an increase in superoxide anion activated by NF-kappaB ³². Literature has discussed the role of P2XR in pain and/or inflammation by expression in the central and peripheral terminals and spinal cord. These P2R receptors are the therapeutic target for a number of naturalproducts ³³. In this discussion another important plant is Turmeric (Curcuma longa) contains curcumin, zingiberene, demethoxycurcmin, bisdemethoxycurcumin, curcumenol, eugenol. These constituents possess antioxidant, anti-inflammatory, anti-mutagenic and anti-HIV activity ^{34, 35, 36}.

Anti Microbial: To fight with problem of resistance to anti-microbial compounds phyto-constituents are being explored ^{37, 38}. A number of heterocyclic nitrogenous compounds (alkaloids) possess antimicrobial action such as diterpenoid alkaloids (Ranunculaceae) and glycoalkaloid solamargine from the berries of Solanum khasianum. The highly aromatic planar quaternary alkaloidal structure of berberine and harmane causes intercalation with DNA and are highly active against trypanosomes ³⁹. The hydrophobic cation of berberine (isoquinoline alkaloid) is an excellent DNA intercalator. To show its broad-spectrum range including bacteria, fungi, protozoa and viruses it targets RNA polymerase, gyrase and topoisomerase IV. Its accumulation in cells is assisted by membrane potential ⁴⁰. The redox potential of quinone-hydroquinone pair is of importance like ubiquinone (coenzyme Q) in mammalian electron transport systems. Some enzymes help for this system such as polyphenoloxidase which convert hydroxyl amino acids into quinines for examples tyrosine. Quinone brings its effect by forming complex with the protein that is responsible for its antimicrobial effects ³⁹. Other secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids are also responsible for the anti-microbial activity ⁴¹. In a disk diffusion study against Streptococcus pyogenes, Staphylococcus aureus, E.coli and P. aeruginosa the result showed highest antibacterial activity with methanolic extract of C. longa and C. molmol against S. pyogenes and S. aureus (19 mm) respectively while minimum activity was observed with aqueous extract of P. anisum against E. coli and P.aueroginosa (7 mm) ⁴². The mature biofilms of Listeria monocytogenes on polystyrene plates and stainless-steel coupons matrices were inactivated with different plant-derived antimicrobials. The result found showed sub-inhibitory concentrations as given-trans-cinnamaldehyde (TC 0.50, 0.75 mM), carvacrol (CR 0.50, 0.65 mM), thymol (TY 0.33, 0.50 mM), and eugenol (EG 1.8, 2.5 mM), and whereas 5.0 and 10.0 mM (TC, CR), 3.3 and 5.0 mM (TY), 18.5 and 25.0 mM (EG) as the concentration for inactivating mature biofilms ⁴³.

CNS Action: Sarsasapogenin, a sapogenin found in Rhizoma Anemarrhenae showed its effect on learning ability and memory of aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1– 40 (Aβ1 –40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalismagnocellularis. The new approach for regulation of learning and memory was presented and the result of study indicated for the modification of the progression of disease ⁴⁴.

Anti-cancer Action: Several flavonols, flavones, flavanones, and the isoflavone are reported to have potent antimutagenic activity ⁴⁵. The carbonyl group at 4^th position of the flavone nucleus is essential for their activity. Flavonoids work against cancer through a wide range of mechanism as these may down regulate the mutant p53 protein, arrest the cell cycle or act via. tyrosine kinase and expression of Ras proteins or may influence the binding of estrogen on the respective receptors ²². In a study involving human breast cancer cell line MDA-MB468 quercetin (3,3',4',5,7-pentahydroxyflavone) was found to decrease the activity of mutated p53 protein in a time and dose dependent manner ⁴⁶. Paclitaxel (Taxol), a terpenoid, found in endangered Pacific yew- Taxus brevifolia (family Taxacae) has specific and reversible stoichiometric interaction with β-tubulin in the microtubule to inhibit cell division, blocking cell mitosis, stabilizing cytoplasmic microtubules. This not only plat anti-cancer role but is also being screened for its activity in other diseases like Alzheimer and coronary heart disease. Another commonly used natural compound is curcunmin which has antioxidant, anti-inflammatory, anti-microbial and anti-cancer activity so finds its use in multiple ways as in case of diabetes, allergies, arthritis and alzheimer’s disease ⁴⁷.

Study conducted on RT4V6 and KU7bladder cancer cells showed that curcumin is assisting in DNA fragmentation and helps to apoptosis ⁴⁸. Garlic (Allium sativum) is very well known for its antimicrobial, antithrombotic, lipid lowering and anti-cancer activity. But the chemopreventive activity is due to the content of organo sulfur compounds like S allylcysteine and S-allylmercapto-L-cystein which exhibit radical scavenging activity. In several animal model S –allylcysteine inhibits the growth of chemically induced and transplantable tumors ⁴⁹.

Astaxanthin a carotenoid, is characterized by its polyene chain with polar entities at both the ends. The chiral centers in C-3 and C-3’ has –OH groups that generates two enantiomers (3S, 3’S), (3R, 3’R) and one mesomer (3R, 3’S) where the first one is naturally predominant. Like β-carotene and other xanthophylls, such as lutein, canthaxanthin and zeaxanthin, it has common semi-symmetric layout with two terminal carbon rings flanking an extended double-bond hydrocarbon chain, also referred to as the polyene chain but the presence of hydroxyl and keto moieties on both ends make its structure distinctive from other carotenoids ⁵⁰. GCS-100 is a polysaccharide derived from citrus pectin ⁵¹. It induces apoptosis by activating caspase-8 and caspase-3 along with proteolytic cleaving of poly(ADP-ribose) polymerase enzyme and affecting antiapoptotic protein Bcl-2, heat shock protein-27, and nuclear factor-kappaB; and prevent vascular endothelial growth factor-induced migration of multiple myeloma cells ⁵². An aromatic phytochemical is found in peanuts (Arachishypogaea) which is called resveratrol existing in cis and trans forms. It causes inhibition of cyclooxygenase activity and suppresses TNF-α-induced activation of nuclear transcription factors NF- B etc. to reduce the oxidative stress and lipid peroxidation ⁵³. The catechins found in green tea like (-)-epicatechin, (-) epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechin-3-gallate ⁵⁴ out of these EGCG may be the most effective as anticancer agent. Where the multi-potency of last one make it a promising multiple-targeted anticancer agent. It causes inhibition of mitogen activated protein kinases, growth factor-related cell signaling, activation of activator protein 1, topoisomerase I, matrix metalloproteinases and other potential targets ⁵⁵.

Study on Capsaicin (8-methyl-N-vanillyl-6-nonenamide) caused apoptosis in highly metastatic B16-F10 murine melanoma cells. It brings about multiple processes to execute its effects such as nuclear condensation, internucleosomal DNA fragmentation, in situ terminal nick-end labeling of fragmented DNA and release of mitochondrial cytochrome c, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase in a dose-dependent manner. In the experiment a slight down regulation in Bcl-2 expression was found ⁵⁶.

Chemical Modification of Natural Compounds: Natural products are good template and chemical models for developing newer analogues which are more efficient than the previous one. Such examples are synthetic analogues like meperidine (Demerol), pentazocine (Talwin), and propoxyphene (Darvon) which were developed from the structural template of opiate alkaloid morphine and codeine. Likewise, another example is of aspirin which is the derivative of naturally occurring salicylic acid obtained from willows (Salix spp.) ⁵⁷. Thiocolchicoside, a semi-synthetic glycoside of colchicinesis used in the treatment of gout and as muscle relaxant. An astonishing example is the structural modification of radical changes in glycone part of anthracycline antitumor antibiotics which is called annamycin.

2-deoxyglycosidic bond was introduced with a liability for enzymatic and chemical break down. Introduction of an equatorial NH₂ group act as a DNA minor grove anchoring element ⁵⁸. The calanolide compounds reported here are the first non-nucleoside analogues having dual activity against HIV-1 and HCMV (human cytomegalovirus). Plant-derived and semi-synthetic calanolide compounds with anti-HIV-1 activity were tested for anti-human cytomegalovirus activity. It was found that there is co-relation between anti- HCMV activity and anti-HIV-1 ⁵⁹. The semi synthetic 12-keto derivatives inclinated to possess more anti-HCMV activity than the corresponding 12-OH congeners, which possess more anti-HIV-1 action. It appeared that the double bond between 7th and 8th position in the chromene ring holds its effect for both the activities. If the double bond is reduced, then it will lead to increase in EC 50 values and toxicity ⁶⁰.

Four protozoan species of the genus Plasmodium (P. falciparum, P. malariae, P. ovale, and P. vivax) are responsible for malaria. Plant derived and semi-synthetic drugs quinine, chloroquine, mefloquine and artemisinin are used for treatment of malaria. Likewise, several indole alkaloids, derived from African medicinal plants also possess in-vitro anti-malarial activity such as 6-(3- methyl-but-2-enyl)-1,3-dihydro-indol-2-one, 3-[6-(3-methyl-but-2-enyl) - 1H - indolyl] - 6 - (3 – methyl – but – 2 - enyl)-1H-indole or annonidine F. These were found to be active against the multidrug resistant strain K1 of P. falciparum (IC 50 = 21 µgmL-1 for each compound) in-vitro testing ⁶¹. A number of natural naphthoquinones (lapachol, β-lapachone and its α-isomer) had shown trypanocidal activities against Trypanosomacruzi parasites which is responsible for Chagas disease. These natural quinones were structurally modified for developing new antichagasic ⁶².

55P0110 is a semi synthetic analogue of multiflorine which showed its anti-hyperglycaemic role with a low risk for fasting hypoglycaemia in mice. Actually, different semi synthetic analogues were designed. Out of which on study it was found that gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions but 55P0110 (90 mg/kg) lacked such an effect ⁶³. Another such example is found with the modification of lactone ring. The lactone ring is involved in inhibition of important enzyme by causing conformational changes. The heterocyclic ring replacement is of being noticed. As replacement by furan ring decreases interaction energy by 2.8 kJ/mol, the approximate energetic contribution of lactone hydrogen bond. Pyrrolidone instead of furanone prominently decreases enzyme inhibition. As sulphur is also hydrogen bond acceptor so replacement by it has unmodified interaction energy ⁶⁴. More potent semi-synthetic anti-malarial analogs of artemisinin with therapeutically important 1,2,4-trioxane core were synthesized ⁶⁵. The first-generation semi-synthetic analogs of artemisinin were prepared to solve the solubility problem. The basic strategy was reduction to its dihydro-derivative (dihydroartemissinin) by sodium borohydride and the lactol was converted to its ether (artemether (a), arteether (b), artelinic acid (c)) and ester (sodium artesunate) (d)) derivatives.

Metabolically more stable 10-phenoxy derivatives were designed which were found to inhibit the P-450 mediated oxidative metabolic formation of dihydroartemissinin. The 10- phenoxy derivatives contains a P-450 resistant aryl group in place of the alkyl group in the first-generation analogs, thus prevents dearylation and its subsequent O- glucuronidation to form the inactive polar conjugate. The pH gradient and the weak base “ion - trapping” effect have generated the aza analogs. The nitrogenous analogs are trapped in the paracite due to protonation by acidic condition of food vacuole ⁶⁶. Plant derived betulinic acid which is a pentacyclic lupine type triterpene, has shown selective inhibition of the growth of human melanoma cells (neuroblastoma and cancerous cells of ovary) in-vitro as well as in-vivo.

The finding of study speaks for the enhancement of differentiation and apoptosis of primary leukemia cells. Its several semi synthetic analogues were synthesized and evaluated. Derivatives with cyanoenone functionality in ring A were found to be highly active whereas betulinic acid was inactive in RAW cell assay. A new analogue is significantly more potent and caused significant induction of the anti- inflammatory, cytoprotective enzyme, heme oxygenase-1, in the liver, while betulinic acid was ineffective at this low dose ⁶⁷. Some other derivatives were found to be more potent than betulinic acid for inhibiting inducible NO-synthase, activating phase 2 cytoprotective enzymes and inducing apoptosis in cancer cells. The cyano group is playing a crucial role as addition of a cyano-enone functionality in the A ring which enhances the cytoprotective action but replacement of cyano group with a methoxycarbonyl increases apoptosis process ⁶⁸.

Future Scenario of Development of New Drugs from Natural Product Research: A data of year 1996 revealed a good number of prescriptions. An important area of research and development covers natural compounds. About over 50% of the top 20 drugs were linked to natural product research. A number of plants from the 2,50,000 species are still to be explored. After the research done with natural plants still there are many more areas where the same molecules could also be proved useful like as anticancer, antiviral and anti-fertility drugs. This strategy is like targeting multiple targets with a single stone ⁶⁹.

Bilateral Picture of Drug Discovery from Natural Resources: The natural template-based drug development program is associated with few specific advantages: Reduction of pressure on the resource. Drug development from Rauwolfia serpentina, Digitalis purpurea etc. are the good example to quote. This approach actually amplifies the therapeutic potential of drug molecule in terms of removing the limitation associated with like podophyllin (obtained from Podophyllum hexandrum) suffers with dose-limiting toxicity but its semi-synthetic derivative etoposide is free from this problem to a great extent. Exploring drug from natural resources also suffer from some disadvantages like exploitation of plants for the need of getting the basic template from plants. For instance, anticancer molecules like etoposide, paclitaxel, docetaxel, topotecan and irinotecan are utilising its highly vulnerable plant resources for getting the starting material since a complete synthesis is not possible. On the other hand, it is expected that some 25,000 plant species would cease to exist by the end of this century ⁷⁰.

DISCUSSION: This review present the combine diversified approach which includes the role of phyto-constituents from the level of genetic control and this creates interest of researcher towards exploring and unlocking the chemical treasure of plants. The role of phytoconstiuents have their importance at the level of protein targeting, enzymatic control, DNA targeting, gene expression control etc. The compatibility of these natural pharmacophore has good frequency match in biological chemistry of humans.

This surprising pairing of phytoconstituents with our biomolecules has deep impact to an extent that it can potentially modulate the biochemical processes of body to bring the changes in bio indication from disease to healthy status. This is quite interesting when the mechanism of phyto-molecules is viewed and the structural beauty of these molecules are explored for the generation of radicals, ions, complex and chelate formation through different chemical bond formation and release of chemical bond energy but they help the body’s natural mechanism unlike the synthetic drug which involve their typical pathological sense.

Previously there are reviews ^{71, 72} over herbal structures in context with therapeutics. But this review not only reveals the link between phyto-molecule and their targets but also it presents the wider picture of these phyto-constituents in regard to the structural basis where this includes enantiomeric isolation and semi-synthetic analogue approach. The semi synthetic analogues are the chemically engineered derivative which handles the structural regards towards surpassing pharmacokinetics and pharmacodynamic performance of parent molecule. This is noticeable that development of semi-synthetic approach solves the threat of plants being exhausted.

Phyto-molecules and their semi-synthetic analogues are the magical molecules which leave their synthetic competitor behind in terms of better desired action, long term effect and minimal or no side effects. Even the small functionality is of importance like amino group ⁵⁷ ketone, double bond chemistry ⁵⁹ lactone ring, heterocyclic feature of rings modulates the interaction level and brings the enhancement of desired action ⁶⁴ and hydrophobic nature of aryl group at 10^th position in artemisinin ⁶⁶. The antioxidant properties of these compounds reduce the toxicity of other drugs also ⁷¹. The chirality in the natural constituents leads the synthesis to the asymmetric synthetic or semi-synthetic research ⁵⁰. When synthetic approach gets blind the phytomolecules unfold the hidden side of prevention and cure of disease. So, the traditional knowledge with modern technical approach can lead to finding of newer better and potential therapeutic molecules. In the discussion it should not be left behind that the phytoconstituents are not only implemented as direct therapeutic agents but also play safe role towards our health in some other way like in form of cosmetic and several herbal preparation for use as toiletries which utilize herbal extract (Diagram 2) ⁷³ which serve not only for the purpose of fragrance and appearance but also exhert their role as anti-oxidants, anti-inflammatory, anti-microbials, free radical scavengers, anti-aging and wound healers etc

DIAGRAM 2: BAR CHART SHOWING DEMAND VALUE (BILLION US DOLLAR) OF HERBAL EXTRACT IN COSMETIC AND TOILETRIES IN RESPECTIVE YEARS (Y AXIS)

CONCLUSION: The compounds from the natural sources have the chemistry which is compatible to a number of therapeutic targets in body. These are generally having either no or minimal side effects but their comparatively high fruitful therapeutic action make these liable to be explored further. On account of avoiding the danger of exploitation, a balanced approach is required in this area so that these can be preserved. Semi-synthetic analogue production may be a beneficial because here compounds are modified chemically so that any limitation related to natural compounds may be excluded and the desired properties can be introduced in terms of improved therapeutic potency or modified physicochemical aspects for easy administration to body. The utilization and research in this realm may lead to the treatment of those diseases which are till now having no solution or a new better way of treatment may be developed than the existing one.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: The author declares that there are no conflicts of interest regarding the publication of this paper.

REFERENCES:

1. Calixto JB: Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents). Brazilian Journal of Medical and Biological Research  2000; 33(2): 179-89
2. Hauptman PJ and Kelly RA: Digitalis. Circulation 1999; 99(9): 1265–70.
3. Bhowmik D, Chiranjib D and Kumar SKP: Traditional herbal drugs: digitalis and its health benefits. International Journal of Pharmaceutical and Bio Medical Science 2010; 1: 16-19.
4. Bohn SK, Ward NC, Hodgson, JM and Croft KD: Effects of tea and coffee on cardiovascular disease risk. Food and Function 2012; 3: 575-91.
5. Hung HY, Qian K, Morris-Natschke SL, Hsu CS and Lee KH: Recent discovery of plant-derived anti-diabetic natural products. Natural Product Reports 2012; 29: 580-606.
6. Olokoba AB, Obateru OA and Olokoba LB: Type 2 diabetes mellitus: a review of current trends. Oman Medical Journal 2012; 27(4): 269–73.
7. Coman C, Rugina OD and Socaciu C: Plants and natural compounds with antidiabetic action. Notulae Botanicae Horti Agrobotanici Cluj-Napoca 2012; 40: 314-25.
8. Harvey AL: Plant natural products in anti-diabetic drug discovery. Current Organic Chemistry 2010; 12: 1670-77.
9. Li Y, Kim J, Li J, Liu F, Liu X, Himmeldirk K, Ren Y, Wagner TE and Chen X: Natural anti-diabetic compound 1,2,3,4,6-penta-O-galloyl-D-glucopyranose binds to insulin receptor and activates insulin-mediated glucose transport signaling pathway. Biochemical and Biophysical Research Communications 2005; 336: 430-37.
10. Gawade BV and Fegade SA: Rauwolfia (Reserpine) as a potential antihypertensive agent: a review. International Journal of Pharmaceutical and Phytopharmacological Research 2012; 2(1): 46-49.
11. Tabassum N and Ahmad F: Role of natural herbs in the treatment of hypertension. Pharmacognosy Reviews 2011; 5: 30–40.
12. Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH and Shayegh J: Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids Pharmacognosy Reviews 2013; 7(14): 199–212.
13. Li JX, Xue B, Chai Q, Liu ZX, Zhao AP and Chen LB: Antihypertensive effect of total flavonoid fraction of Astragalus complanatus in hypertensive rats. Chinese Journal of Physiology 2005; 48: 101-06.
14. Xue B, Li J, Chai Q, Liu Z and Chen L: Effect of total flavonoid fraction of Astragalus complanatus R. Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine 2008; 15(9): 759-62.
15. Ben Bakrim W, Ezzariai A, Karouach F, Sobeh M, Kibret M, Hafidi M, Kouisni L and Yasri A: Eichhornia crassipes (Mart.) Solms: A comprehensive review of its chemical composition, traditional use and value-added products. Frontiers in Pharmacology 2022; 13: 842511.
16. Kumar S, Joseph L, George M and Sharma A: A review on anticoagulant/antithrombotic activity of natural plants used in traditional medicine. International Journal of Pharmaceutical Sciences Review and Research 2011; 8(1): 70-74.
17. Afonne OJ, Orisakwe OE, Obi E, Orish C, Akumka DD: Some pharmacological properties of Synclisia scabrida III. Indian Journal of Pharmacology 2000; 32(3): 239-41.
18. Palipoch S: A review of oxidative stress in acute kidney injury: protective role of medicinal plants-derived antioxidants. African Journal of Traditional, Complementary and Alternative Medicines 2013; 10(4): 88-93.
19. Moure A, Cruz JM, Franco D, Domı́nguez JM, Sineiro J, Dominguez H, Nunez MJ and Parajo JC: Natural antioxidants from residual sources. Food Chemistry 2001; 72(2): 145-71.
20. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PV, Martins N and Sharifi-Rad J: Resveratrol: A double-edged sword in health benefits. Biomedicines 2018; 6(3): 91.
21. Brewer MS: Natural antioxidants: sources, compounds, mechanisms of action, and potential applications. Comprehensive Reviews in Food Science and Food Safety 2011; 10(4): 221-47.
22. Kumar S and Pandey AK: Chemistry and biological activities of flavonoids: an overview. The Scientific World Journal 2013; 2013: 162750
23. Hussein MA and Boshra SA: Antitumor and structure antioxidant activity relationship of colchicine on Ehrlich ascites carcinoma (EAC) in female mice. International Journal of Drug Delivery 2013; 5(4): 430.
24. Ahmed MF and Nizam ASR: Comparative hepatoprotective activities of selected Indian medicinal plants. Global Journal of Medical Research Pharma Drug Discovery Toxicology and Medicine 2013; 13: 15-21.
25. Rajeswary H, Vasuki R, Samudram P and Geetha A: Hepatoprotective action of ethanolic extracts of Melia azedarach Linn. and Piper longum Linn and their combination on CCl4 induced hepatotoxicity in rats. Indian J of Experimental Biology 2011; 49(4): 276-81.
26. Zhu W, Jia Q, Wang Y, Zhang Y and Xia M: The anthocyanin cyanidin-3-O-β-glucoside, a flavonoid, increases hepatic glutathione synthesis and protects hepatocytes against reactive oxygen species during hyperglycemia: Involvement of a cAMP–PKA-dependent signaling pathway. Free Radical Biology and Medicine 2012; 52(2): 314-27.
27. Saller R, Meier R and Brignoli R: The use of silymarin in the treatment of liver diseases. Drugs 2001; 61: 2035-63.
28. He Q, Kim J and Sharma RP: Silymarin protects against liver damage in BALB/c mice exposed to fumonisin B1 despite increasing accumulation of free sphingoid bases. Toxicological Sciences 2004; 80(2): 335-42.
29. Jyothi BA, Mohanalakshmi S and Anitha K: Protective effect of Mirabilis jalapa leaves on anti-tubercular drugs induced hepatotoxicity. The Asian Journal of Pharmaceutical and Clinical Research 2013; 6(3): 221-4.
30. Yuan G, Wahlqvist ML, He G, Yang M and Li D: Natural products and anti-inflammatory activity. Asia Pacific Journal of Clinical Nutrition 2006; 15(2): 143-52.
31. Boukhatem MN, Ferhat MA, Kameli A, Saidi F and Kebir HT: Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs. Libyan Journal of Medicine 2014; 9(1): 25431.
32. Speranza L, Franceschelli S, Pesce M, Menghini L, Patruno A, Vinciguerra I, De Lutiis MA, Felaco M, Felaco P and Grilli A: Anti-inflammatory properties of the plant Verbascum mallophorum. Journal of Biological Regulators and Homeostatic Agents 2009; 23(3): 189-95.
33. Soares-Bezerra RJ, Calheiros AS, da Silva Ferreira NC, da Silva Frutuoso V and Alves LA: Natural products as a source for new anti-inflammatory and analgesic compounds through the inhibition of purinergic P2X receptors. Pharmaceuticals 2013; 6(5): 650-8.
34. Rane R, Gangolli D, Patil S, Ingawale K and Kundanwal S: Analytical study of curcumin content in different dosage forms containing turmeric extract powder and turmeric oleoresin. Inter Research J of Pharmacy 2013; 4: 182-5.
35. Kocaadam B and Şanlier N: Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Critical Reviews in Food Science and Nutrition 2017; 57(13): 2889-95.
36. Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, Limtrakul P, Badmaev V and Aggarwal BB: Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis 2007; 28(8): 1765-73.
37. Hofling JF, Anibal PC, Obando-Pereda GA, Peixoto IA, Furletti VF, Foglio MA and Gonçalves RB: Antimicrobial potential of some plant extracts against Candida species. Brazilian Journal of Biology 2010; 70: 1065-8.
38. Khare T, Anand U, Dey A, Assaraf YG, Chen ZS, Liu Z and Kumar V: Exploring phytochemicals for combating antibiotic resistance in microbial pathogens. Frontiers in Pharmacology 2021; 12: 720726.
39. Cowan MM: Plant products as antimicrobial agents. Clinical Microbiology Reviews 1999; 12(4): 564-82.
40. Savoia D: Plant-derived antimicrobial compounds: alternatives to antibiotics. Future Microbiology 2012; 7(8): 979-90.
41. Sahu P, Matlam M, Dubey RD, Paroha S, Chatterji S, Verma S and Chatterjee T: Natural plant products with potential antimicrobial activity. Research Journal of Pharmacognosy and Phytochemistry 2011; 3(1): 1-9.
42. Al-Daihan S, Al-Faham M, Al-shawi N, Almayman R, Brnawi A and Shafi Bhat R: Antibacterial activity and phytochemical screening of some medicinal plants commonly used in Saudi Arabia against selected pathogenic microorganisms. Journal of King Saud University-Science 2013; 25(2): 115-20.
43. Upadhyay A, Upadhyaya I, Kollanoor-Johny A and Venkitanarayanan K: Antibiofilm effect of plant derived antimicrobials on Listeria monocytogenes. Food Microbiology 2013; 36(1): 79-89.
44. Hu Y, Xia Z, Sun Q, Orsi A and Rees D: A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Research 2005; 1060(1-2): 26-39.
45. Panche AN, Diwan AD and Chandra SR: Flavonoids: an overview. Journal of Nutritional Science 2016; 5: 47.
46. Avila MA, Velasco JA, Cansado J and Notario V: Quercetin mediates the down-regulation of mutant p53 in the human breast cancer cell line MDA-MB468. Cancer Research 1994; 54(9): 2424-8.
47. Hewlings SJ and Kalman DS: Curcumin: A review of its effects on human health. Foods 2017; 6(10): 92.
48. Mou X, Kesari S, Wen PY and Huang X: Crude drugs as anticancer agents. International Journal of Clinical and Experimental Medicine 2011; 4(1): 17.
49. Thomson M and Ali M: Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent. Current Cancer Drug Targets 2003; 3(1): 67-81.
50. Yang Y, Kim B and Lee JY: Astaxanthin structure, metabolism, and health benefits. Journal of Human Nutrition and Food Science 2013; 1(1003): 1-003.
51. Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG and Cotter FE: GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood, the Journal of the American Society of Hematology 2010; 115(19): 3939-48.
52. Chauhan D, Li G, Podar K, Hideshima T, Neri P, He D, Mitsiades N, Richardson P, Chang Y, Schindler J and Carver B: A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Research 2005; 65(18): 8350-8.
53. Udenigwe CC, Ramprasath VR, Aluko RE and Jones PJ: Potential of resveratrol in anticancer and anti-inflammatory therapy. Nutrit Revie 2008; 66(8): 445-54.
54. Musial C, Kuban-Jankowska A and Gorska-Ponikowska M: Beneficial properties of green tea catechins. International J of Molecular Sciences 2020; 21(5): 1744.
55. Chen L and Zhang HY: Cancer preventive mechanisms of the green tea polyphenol (-)-epigallocatechin-3-gallate. Molecules 2007; 12(5): 946-57.
56. Jun HS, Park T, Lee CK, Kang MK, Park MS, Kang HI, Surh YJ and Kim OH: Capsaicin induced apoptosis of B16-F10 melanoma cells through down-regulation of Bcl-2. Food and Chemical Toxicology 2007; 45(5): 708-15.
57. Balandrin MF, Klocke JA, Wurtele ES and Bollinger WH: Natural plant chemicals: sources of industrial and medicinal materials. Science 1985; 228(4704): 1154-60.
58. Grynkiewicz G, Szeja WI and Boryski J: Synthetic analogs of natural glycosides in drug discovery and development. Acta Poloniae Pharmaceutica 2008; 65(6): 655-76.
59. Xu ZQ, Kern ER, Westbrook L, Allen LB, Buckheit RW, Tseng CK, Jenta T and Flavin MT: Plant-derived and semi-synthetic calanolide compounds with in-vitro activity against both human immunodeficiency virus type 1 and human cytomegalovirus. Antiviral Chemistry and Chemotherapy 2000; 11(1): 23-9.
60. Amoa Onguene P, Ntie-Kang F, Lifongo LL, Ndom JC, Sippl W and Mbaze LM: The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmacological evaluation of alkaloids and terpenoids. Malaria Journal 2013; 12: 1-26.
61. Cragg GM and Newman DJ: Natural products: a continuing source of novel drug leads. Biochimica et Biophysica Acta 2013; 1830(6): 3670-95.
62. Salas CO, Faundez M, Morello A. Diego Maya J and Tapia RA: Natural and synthetic naphthoquinones active against Trypanosoma cruzi: An initial step towards new drugs for Chagas disease. Current Medicinal Chemistry 2011; 18: 144-61.
63. Brunmair B, Lehner Z, Stadlbauer K, Adorjan I, Frobel K, Scherer T, Luger A, Bauer L and Fürnsinn C: 55p0110, a novel synthetic compound developed from a plant derived backbone structure, shows promising anti-hyperglycaemic activity in mice. PLoS One 2015; 10(5): 0126847.
64. Melero CP, Medarde M and San Feliciano A: A short review on cardiotonic steroids and their aminoguanidine analogues. Molecules 2000; 5(1): 51-81.
65. Rudrapal M, Chetia D and Singh V: Novel series of 1,2,4-trioxane derivatives as antimalarial agents. Journal of Enzyme Inhibition and Med Chem 2017; 32(1): 1159-73.
66. Ploypradith P: Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs. Acta Tropica 2004; 89(3): 329-42.
67. Honda T, Liby KT, Su X, Sundararajan C, Honda Y, Suh N, Risingsong R, Williams CR, Royce DB, Sporn MB and Gribble GW: Design, synthesis, and anti-inflammatory activity both in-vitro and in-vivo of new betulinic acid analogues having an enone functionality in ring A. Bioorganic and Med Chem Letters 2006; 16(24): 6306-9.
68. Liby K, Honda T, Williams CR, Risingsong R, Royce DB, Suh N, Dinkova-Kostova AT, Stephenson KK, Talalay P, Sundararajan C and Gribble GW: Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. Molecular Cancer Therapeutics 2007; 6(7): 2113-9.
69. Phillipson JD: Phytochemistry and medicinal plants. Phytochemistry 2001; 56(3): 237-43.
70. Katiyar C, Gupta A, Kanjilal S and Katiyar S: Drug discovery from plant sources: An integrated approach. Ayu 2012; 33(1): 10.
71. Karimi A, Majlesi M and Rafieian-Kopaei M: Herbal versus synthetic drugs; beliefs and facts. Journal of Nephropharmacology 2015; 4(1): 27.
72. Nisar B, Sultan A and Rubab SL: Comparison of medicinally important natural products versus synthetic drugs-a short commentary. Natural Products Chemistry & Research 2018; 6(2): 308.
73. Nirmal SA, Pal SC, Otimenyin SO, Aye T, Elachouri M, Kundu SK, Thandavarayan RA and Mandal SC: Contribution of herbal products in global market. The Pharma Review 2013; 2013: 95-104.
    

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    Dubey S, Shukla P, Shukla P and Alok S: Exhaustive review on therapeutical role of some phytoconstituents and their chemical alteration. Int J Pharm Sci & Res 2024; 15(2): 382-91. doi: 10.13040/IJPSR.0975-8232.15(2). 382-91.

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