## 5 Biodiscovery Potential of Plants Growing under Ex-Situ Abiotic Stresses  
Natural products, including PSMs, have been a significant source of medicines. According to [PERSON] and [PERSON], between 1981 and 2010, 1073 small molecules (mol. wt. \(<\) 1000 Da) were approved as new chemical entities, out of which more than half were from natural products [270]. An additional 321 small molecules were reported in another review published in September 2019 [271]. According to [PERSON] et al. [272], in their review covering natural products-derived drugs between 2008-2013, 25 drugs were launched since 2008, and additional 31 compounds were in the last stage clinical trial (phase III). According to the database on www.clinicaltrials.gov (accessed 5 September 2021), four compounds have advanced to phase-IV clinical trial, sixteen have completed phase-III, nine have not yet completed phase-III, and two compounds have been withdrawn. The four compounds that have advanced to clinical trial phase-IV are oritavancin (anti-bacterial), ipraglifilozin, tofoglifozin (anti-diabetic, type II diabetes), and vorapaxar (anti-thrombotic) [272]. Recently, pharmaceutical industries and researchers have renewed their interest in PSMs due to advancements in cutting-edge technology, including various chromatography and high-resolution spectroscopy tools and omic  
Figure 7: Chemical structure of compounds known to accumulate in plants under various abiotic stress conditions.  
Interestingly, not many PSMs were subjected to clinical trials. The reasons are varied. One of the continuing challenges for drug discovery from plant sources is obtaining enough sample extracts and compounds for testing in vitro and in vivo disease models. This bottleneck is heightened for species in the IUCN red list of threatened or endangered species prohibited for large sample collection, even if they show biological hits. While cultivating pharmaceutically interesting plant species may be a solution, it is not always possible to culture the organism outside its natural habitat. Even when possible, relevant natural products may not be produced outside their natural habitat [273]. Alternatively, plants affected by climate change could be a potential source of novel drug leads, considering the vast diversity of phytochemicals produced by them in response to various abiotic stress conditions (Table 1).  
Climate change rapidly and severely affects plant ecosystems; for instance, mountain-top ecosystems are sensitive to small shifts in temperature and precipitation patterns [274]. Several studies on the mountaintops of the Asia-Pacific region [275], Oceania [276], and Europe [277] have reported accelerated plant ecological responses, including distribution, ecophysiology, and interaction with other organisms due to climatic changes. In overcoming climate change-induced/or abiotic stress and finding an optimal climate niche, plants produce diverse PSMs, which could be of pharmaceutical interest. For example, the synthesis of plant terpenids increases under heat, cold, and O\({}_{3}\) stress, and the yield of many biologically active compounds also increases in plants grown in simulated environments of various abiotic stress conditions (Table 1). Abiotic stresses elicit bioactive compound synthesis [278], such as phenylpropanoids biosynthesis (mainly through shikimate pathway), causing an accumulation of compounds with defense or signaling functions (e.g., phenolics, flavonoids, and alkaloids) [279]. Similarly, it is reported that drought stress increases the concentration of camptothecin (anticancer alkaloid) in _Campptotheca acuminata_[116; 117] and morphine (analgesic) concentrations in _Papaver somniferum_. The increased accumulation of PSMs in response to stress indicates that there may be novel bioactive alkaloid(s) in climate change-affected plants awaiting discovery. Abiotic stress factors under conditioned environment can potentially improve the yield of bioactive compounds in plants.