Plant secondary metabolites (PSMs) are small molecules with diverse chemical structures and biological activities. Unlike primary metabolites, which are the main drivers of essential life functions, including cell formation, PSMs are neither necessary for primary life functions nor possess high-energy bonds [1]. However, PSMs play essential secondary physiological and biochemical functions that ensure plant fitness and survival, particularly concerning their interactions with the environment and coping with biotic and abiotic stress [1]. These factors, especially abiotic stressors (nutrient deficiencies, seasons, salinity, wounding, drought, light, UV radiation, temperature, greenhouse gases, and climate changes), cause significant perturbations in chemotypes and levels of PSMs production. For example, plants produce more terpenoids when exposed to high temperatures [2], and UV-B (280–315 nm) radiation induces tree foliage to produce more phenolic acids and flavonoids as protective pigments ^[3][4][3,4]. Phenolics and flavonoids are well-known for their antioxidative and anti-inflammatory properties ^[5][6][7][5,6,7]. Similarly, the production of antioxidative compounds such as glutathione, g-aminobutyric acid (GABA), terpenoids, and volatile organic compounds (VOCs) increases under elevated O₃ [8].

PSMs are vital for human health and form many pharmaceutical drugs’ backbone. Indeed, more than 25% of the existing drugs belong to PSMs [9]. The most popular PSMs-derived drugs are morphine (isolated from Papaver somniferum), digitoxin (isolated from Digitalis purpurea), taxol (isolated from Taxus baccata), artemisinin (isolated from Artemisia annua) and quinine (isolated from Cinchona officinalis), vinblastine and vincristine (isolated from Catharanthus roseus); and aspirin (first isolated as salicylic acid from Filipendula ulmaria). Since plants exposed to various abiotic stress conditions produce many PSMs in higher concentrations as their coping mechanism ^[10][11][12][10,11,12], it presents opportunities for natural product researchers and pharmaceutical companies to explore the biochemical responses of plants to climatic stress for developing many novel therapeutics. However, there is no comprehensive literature review examining the scope of plants affected by abiotic stresses for drug discovery.

2. Reported Pharmacological Properties of PSMs Present in Plants Affected by Ex Situ Abiotic Stresses

Plant protective secondary metabolites are diverse in structure and biological properties, and they have been continuously exploited for pharmaceutical, nutraceutical, and cosmetic uses ^[13][251] (Figure 17). Flavonoids and other phenolic compounds are predominant among secondary metabolites produced in response to climatic/or abiotic stress (Table 1). Flavonoids confer protection against inflammation, allergy, and bacterial infections ^[14][252]. Flavonols (or 3-hydroxy flavones), one of the main subclass of flavonoids, are apparent antioxidants in stressed plants, and they are known to prevent nuclear DNA damage by free radicals like H₂O₂ ^[15][253]. Flavonols are polyaromatic secondary metabolites with three rings, and many of them are bioactive. Many flavonoids possess antiviral properties. For instance, the hydroxy (OH) group in the ring-C of flavonols makes them more effective against herpes simplex virus type I than flavones ^[16][254]. Fisetin is another example of an active flavonoid produced by plants under oxidative stress, preventing membrane lipid peroxidation, DNA damage, and protein carbonylation ^[17][247]. Fisetin showed numerous biological activities such as protection against cell death from oxidative stress, growth, and maintenance of nerve cells (primary cortical neurons from a rat) ^[18][19][248,255]. Fisetin suppresses many inflammatory pathways, including Nuclear Factor-kappa B (NF-kB) pathway, helping prevent cancerous growth ^[20][21][256,257]. Similarly, Hussain et al. ^[22][258] also observed the protective effect of fisetin against smoke-induced oxidative stress and inflammation in rat lungs. Plant UV filters, kaempferol, and quercetin are a few other examples of bioactive flavonoids. Kaempferol is an anti-inflammatory ^[23][259], chemo-protective ^[24][260], and cardio-protective ^[25][261]. Polyphenolic resveratrol is one of the essential stilbene phytoalexin produced by a plant’s defense mechanism, and it possesses antioxidant, anticancer, and anti-estrogenic properties ^[26][262]. The immunoinhibitory compound, calycopterin isolated from the medicinal plant Dracocephalum kotschyi ^[27][168], was elevated upon UV irradiation in Gnaphalium luteo-album ^[28][167]. Tanshinones are other examples of bioactive phenols. In response to severe drought stress, their concentration in the Salvia miltiorrhiza increases, including tanshinone I and tanshinone IIA by 182% and 322%, respectively, compared to 148% under the moderate drought stress ^[29][139]. Tanshinones are known for their anti-inflammatory, antioxidant, and anticancer properties ^[30][263].

Nitrogen-containing compounds, alkaloids, are another group of secondary metabolites widely produced in plants for defense, and they are known to exhibit diverse biological activities, including anti-inflammatory, anti-malarial, and anticancer activities ^[31][264]. The fungistatic activity of α-tomatine (Solanum and Lycopersicon species) in Fusarium oxysporum f. lycopersici (tomato wilt) was the first bioactive alkaloid reported in 1945 by Irving et al. ^[32][69]. Alkaloids and their precursors accumulate more in plants when exposed to various stress factors. For example, Catharanthus roseus, when exposed to UV-B radiation, synthesizes more indole alkaloids and precursors of vinblastine and vincristine increase in hairy roots ^[33][265]. These alkaloids inhibit cell mitosis by destroying microtubules of the mitotic apparatus, blocking cancer cell division ^[34][266]. Bioactive alkaloids accumulate in response to high temperature, drought, and UV-B stresses (Table 1). Indole alkaloid vindoline from Catharanthus roseus (which increases in response to UV-B) showed anti-diabetic (reduces fasting blood glucose level) and anti-inflammatory (reduces pro-inflammatory cytokines, TNF- α and IL-6) properties ^[35][99]. The number of structurally determined specialized plant terpenes exceeds 105, including >12,000 diterpenoids ^[36][267]. Plant terpenoids are diverse and have been a valuable source of medicinal discoveries because terpenoids are natural NF-kB signaling inhibitors with anti-inflammatory and anti-cancer properties ^[37][268]. Examples include monoterpenes (e.g., (−)-menthol and cannabinoids); sesquiterpenes (e.g., artemisinin and thapsigargin); diterpenes (e.g., paclitaxel and ingenol mebutate) and triterpenes found in floral and vegetative parts; triterpenoids; and carotenoids (e.g., steroidal alkaloids, cardenolides, and bixin) (Figure 17). Other compounds are partially derived from a terpene precursor, such as monoterpenoid alkaloids (e.g., strychnine), which are synthesized in part from secologanin (Figure 17), a member of the widespread class of iridoid monoterpenes ^[38][269].

Stress Condition(s)	Plant Species (Family)	PSMs Produced	Effects on PSMs Concentration	Compound Class	Bioactive Compounds	Reported Pharmacological Properties
Cold stress	Catharanthus roseus (Apocynaceae) [39]	(Apocynaceae) [98]	vindoline	Decrease	Alkaloids	vindoline	Antidiabetic [35]	Antidiabetic [99]
Cold stress	Glycine max (Fabaceae) [40]	(Fabaceae) [94]	genistein, daidzein	Increase	Phenolics	genistein, daidzein	Antiproliferative [41][42]	Antiproliferative [95,96]
Cold stress	Solanum lycopersicon (Solanaceae) [43][44]	(Solanaceae) [87,97]	(	Z	)-3-hexenol and (	E	)-2-hexenal (dominant); 1-hexanol and 1,4-hexadienal (smaller quantities)	Increase	Fatty Acyls	(	E	)-2-hexenal	Antibacterial [45]	Antibacterial [100]
Cold stress			β-phellandrene, (	E	)-β-ocimene	Increase	Terpenoids	NA	NA
Cold stress			δ-elemene, α-humulene and β-caryophyllene (dominant); in severe cold: β-elemene is produced.	Increase	Terpenoids	δ-elemene, α-humulene and β-caryophyllene	Antiproliferative [46]; anticancer [47]; anti-inflammatory [48]	Antiproliferative [101]; anticancer [102]; anti-inflammatory [103]
Cold stress	Zea mays (Poaceae) [49]	(Poaceae) [104]	pelargonidin	Increase	Phenolics	pelargonidin	Antithrombotic [50]	Antithrombotic [105]
Cold stress	Fagopyrum tartaricum (Polygonaceae) [51]	(Polygonaceae) [106]	anthocyanins (e.g.,3-	O	-galactosides) and anthocyanidins (e.g., malvidin)	Increase	Phenolics	anthocyanins	Antioxidant [52]	Antioxidant [107]
Cold stress	Withania somnifera (Solanaceae) [53]	(Solanaceae) [108]	withanolide A, withaferin A	Increase	Terpenoids	withanolide A; withferin A	Neuroprotective [54]; anticancer [55]	Neuroprotective [109]; anticancer [110]
Cold stress	Camellia sinensis (Theaceae) [56]	(Theaceae) [111]	nerolidol glucoside	Increase	Terpenoids	NA	NA
Drought	Amaranthus tricolor (Amaranthaceae) [57]	(Amaranthaceae) [112]	hydroxybenzoic acids (gallic acid, vanillic acid, syringic acid,	p	-hydroxybenzoic acid, salicylic acid, ellagic acid), hydroxycinnamic acids (caffeic acid, chlorogenic acid,	p	-coumaric acid, ferulic acid,	m	-coumaric acid, sinapic acid,	trans	-cinnamic acid), flavonoids (iso-quercetin, hyperoside, rutin).	Increase	Phenolics (Flavonoids)	p	-hydroxybenzoic acid	Antisickling activity [58]	Antisickling activity [113]
Drought	Camellia sinensis (Theaceae) [59]	(Theaceae) [114]	Epicatechins	Increase	Phenolics (Flavonoids)	epicatechins	Antioxidant [60]	Antioxidant [115]
Drought	Camptotheca acuminata (Nyssaceae) [61]	(Nyssaceae) [116]	camptothecin	Increase	Alkaloids	camptothecin	Antitumour [62]	Antitumour [117]
Drought (PEG-induced)	Catharanthus roseus (Apocyanaceae) [63]	(Apocyanaceae) [118]	vinblastine	Increase	Alkaloids	vinblastine	Anticancer [64]	Anticancer [119]
Drought	Cistus clusii (Cistaceae) [65]	(Cistaceae) [120]	epigallocatechin gallate, epicatechin, epicatechin gallate, and ascorbic acid.	Increase	Phenolics (Flavonols)	epigallocatechin gallate	Anticancer [66]; antibacterial [67]	Anticancer [121]; antibacterial [122]
Drought	Crataegus laevigata	,	C. monogyna (Rosaceae) [68]	(Rosaceae) [123]	chlorogenic acid, catechin, (−)-epicatechin	Increase	Phenolics	chlorogenic acid, (−)-epicatechin	Antioxidant [69][70]	Antioxidant [124,125]
Drought	Glycine max (Fabaceae) [71]	(Fabaceae) [126]	trigonelline	Increase	Alkaloids	trigonelline	Antidiabetic [72]	Antidiabetic [127]
Drought	Hypericum brasiliense (Hypericaceae) [73]	(Hypericaceae) [128]	isouliginosin B, rutin, 1,5-dihydroxyxanthone	Increase	Phenolics	isouliginosin B, rutin,	Antinociceptive [74]; Anticancer [75]	Antinociceptive [129]; Anticancer [130]
			betulinic acid		Terpenoids	betulinic acid	Anticancer [76]	Anticancer [131]
Drought	Lupinus angustifolius (Fabaceae) [77]	(Fabaceae) [132]	chinolizidin	Increase	Alkaloids	NA	NA
Drought	Papaver somniferum (Papaveraceae) [78]	(Papaveraceae) [133]	morphine, codeine	Increase	Alkaloids	morphine, codeine	Analgesic [79][80]	Analgesic [134,135]
Drought	Pinus sylvestris (Pinaceae) [81]	(Pinaceae) [136]	abietic acid	Increase	Terpenoids	abietic acid	Antiallergic [82]; anti-inflammatory [83]	Antiallergic [137]; anti-inflammatory [138]
Drought	Salvia miltiorrhiza (Lamiaceae) [29]	(Lamiaceae) [139]	tanshinones, cryptotanshinone	Increase	Terpenoids	cryptotanshinone	Anticancer [84].	Anticancer [140].
Drought	S. miltiorrhiza [29]	[139]	rosmarinic acid	Decrease	Phenolics	rosmarinic acid	Antioxidant [85]	Antioxidant [141]
			salvianolic acid	Increase		salvianolic acids	Antioxidant [86]	Antioxidant [142]
Drought	Scrophularia ningpoensis (Scrophulariaceae) [87]	(Scrophulariaceae) [143]	catalpol, harpagide, aucubin, harpagoside	Increase	Glycosides	catalpol, aucubin	Hepatoprotective [88]; neuroprotective [89]	Hepatoprotective [144]; neuroprotective [145]
Ozone (O	3	) stress	S. lycopersicon [43][44]	[87,97]	α-carotene, β-carotene, violoxanthin	Increase	Terpenoids	β-carotene	Antioxidants [90]; anti-inflammatory [91]	Antioxidants [146]; anti-inflammatory [147]
					isoprene, α-pinene, β-pinene, myrcene, limonene, sabinene, (	E	)-β-ocimene, (	Z	)-β-ocimene, α-humulene, (	E	)-β-farnesene, (	E,E	)-α-farnesene, (	E	)-β-caryophyllene, δ-cadinene	Increase	Terpenoids	α-pinene; myrcene; limonene; α-humulene.	Anti-inflammatory [92]; anti-asthmatic [93]; antioxidant [94]; anti-inflammatory [95]	Anti-inflammatory [148]; anti-asthmatic [149]; antioxidant [150]; anti-inflammatory [151]
O	3	Gingko biloba (Ginkgoaceae) [96]	(Ginkgoaceae) [152]	ginkgolide A	Increase	Terpenoids	ginkgolide A	Neuroprotective [97]	Neuroprotective [153]
Ultraviolet radiation-B (UV-B)	Arabidopsis thaliana (Brassicaceae) [98]	(Brassicaceae) [154]	kaempferol 3-gentiobioside-7-rhamnoside; kaempferol 3,7-dirhamnoside.	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Brassica napus (Brassicaceae) [99]	(Brassicaceae) [155]	quercetin 3-sophoroide-7-glucoside; quercetin 3-sinapyl sophoroside-7-glucoside	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Brassica oleracea (Brassicaceae) [100]	(Brassicaceae) [156]	cyanidine glycosides; sinapyl alcohol	Increase	Phenolics (Flavoboids)	NA	NA
UV-B	C. roseus (Apocynaceae) [101][102]	(Apocynaceae) [157,158]	catharanthine, vindoline	Increase	Alkaloids	catharanthine	Anticancer [103]	Anticancer [159]
	Clarkia breweri (Onagraceae) [104]	(Onagraceae) [160]	eugenol, isoeugenol, methyleugenol, and isomethyleugenol	Increase	Phenolics	eugenol	Antifungal [105]; anti-inflammatory [106]	Antifungal [161]; anti-inflammatory [162]
UV-B	Fagopyrum esculentum (Polygonaceae) [107]	(Polygonaceae) [163]	rutin, quercetin, catechin	Increase	Phenolics	quercetin; catechin	Antioxidant [108]; anticancer and antioxidant [109][110]	Antioxidant [164]; anticancer and antioxidant [165,166]
UV-B	Gnaphalium luteoalbum (Asteraceae) [28]	(Asteraceae) [167]	calycopterin; 3’-methoxycalycopterin	Increase	Phenolics (Flavonoids)	calycopterin	Anticancer [27]	Anticancer [168]
UV-B	G. viravira [111]	[169]	7-O-methyl araneol	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Hordeum vulgare (Poaceae) [112]	(Poaceae) [170]	saponarin; luteolin	Increase	Phenolics (Flavonoids)	saponarin; luteolin	Antihypertensive [113]; antibacterial [114]	Antihypertensive [171]; antibacterial [172]
UV-B	Marchantia polymorpha (Marchantiaceae) [115]	(Marchantiaceae) [173]	luteolin 7-glucuronide; luteolin 3,4’-di-	p	-coumaryl-quercetin 3-glucoside.	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Quercus ilex (Fagaceae) [116]	(Fagaceae) [174]	acylated kaempferol glycosides	Increase	Phenolics (Flavonoids)	kaempferol	Anticancer [117]; anti-inflammatory [118]	Anticancer [175]; anti-inflammatory [176]
Heat stress	C. acuminata [119]	[177]	10-hydroxycamptothecin	Increase	Alkaloids	10-hydroxycamptothecin	Anticancer [120]	Anticancer [178]
Heat stress	Daucus carota (Apiaceae) [121][122][123]	(Apiaceae) [179,180,181]	α-terpinolene	Decrease	Terpenoids	α-terpinolene	Antioxidant and anticancer [124]	Antioxidant and anticancer [182]
			α-caryophyllene, β-farnesene	Increase		NA	NA
			anthocyanins, coumaric and caffeic acid;	Increase	Phenolics	p	-coumaric acid and caffeic acid	Antioxidant [125][126]	Antioxidant [183,184]
Heat stress	Q. rubra (Fagaceae) [127]	(Fagaceae) [185]	isoprene (2-methyl-1,3-butadiene)	Increase	Terpenoids	NA	NA
Heat stress	S. lycopersicon [43][44]	[87,97]	β-phellandrene (dominant), 2-carene, α-phellandrene, limonene; increased emission of (	E	)-β-ocimene after treatment above 46 °C; β-caryophyllene.	Increase	Terpenoids	α-phellandrene; β-caryophyllene	Antifungal [128]; anticancer and anti-inflammatory [47][48]	Antifungal [186]; anticancer and anti-inflammatory [102,103]
			α-humulene	Decrease	α-humulene	Anticancer [129]		Anticancer [187]
Heat stress (increased humidity)	Centella asiatica (Apiaceae) [130]	(Apiaceae) [188]	asiaticoside	Increase	Phenolics	asiaticoside	Anti-cellulite agent [131]	Anti-cellulite agent [189]

3. Conclusions

Plants constantly interact with the environment, and climate change has already impacted their diversity, growth, and survival. In order to minimize the impact of various climate change-related stresses (such as warming due to increased greenhouse gas emission, drought, cold, ozone-layer depletion, and harmful UV-radiation), plants produce diverse defense secondary metabolites, mainly phenolic and nitrogen-containing compounds. The biosynthesis of defense compounds in plants (including medicinal plants) is often upregulated, and these compounds are associated with various pharmacological properties, suggesting that plants affected by climate change may be a rich resource for drug discovery. However, most of these studies were conducted in simulated/or artificial environments. Thus, it would be interesting if more such studies (defense compounds produced by plants in response to climatic stress and their bioactivity) could be conducted by using plant samples from their natural habitats that are already challenged by the various climatic stresses.

It is difficult to access various natural products bound by legislation and societal restrictions, including plants, for drug discovery research, particularly plants associated with indigenous knowledge. This limitation remains a considerable challenge for those working with medicinal plants. Other wild plants exposed to various climatic/or abiotic stresses would be an alternative option for drug discovery researchers. Another obstacle in the drug discovery process is obtaining adequate compounds for further biological tests (both in vitro and in vivo). Bioactive compounds increase their concentration in plants exposed to stress, for example, withanolides in Indian ginseng (Withania somnifera) increases in response to cold stress. Culturing plant tissues of interest at a large scale under a conditioned environment using various abiotic stresses can potentially improve the yield of bioactive compounds from plants. Thus, plant tissue culture would be another platform for researchers and pharmaceutical industries to upscale the production of valuable phytochemicals under duress of climate change factors.