Letters in Drug Design & Discovery - Volume 20, Issue 4, 2023

Apoptosis or programmed cell death is a carefully synchronized collapse of cells due to protein degradation and fragmentation of DNA. It is an essential part of the life cycle of every multicellular organism, including worms to humans. Apoptosis plays a major role in cancer development as well. Various studies confirm the potential of many drugs to change the regulation and ratio of pro-apoptotic and antiapoptotic factors. Plants are the best-known source of drugs for various diseases, including cancer. Plant secondary metabolites (alkaloids, terpenes and phenolics) are the major constituents used as drugs. Several studies confirm that these secondary metabolites can induce apoptosis by triggering pro-apoptotic and antiapoptotic factors. This article has studied some of the important secondary metabolites and their mode of action as apoptotic triggering agents.

Background: Phytochemicals and their derivatives/analogues represent over 50% of the current medicines worldwide in clinical use. Despite a significant contribution to the total bioactive natural plant products, aquatic plants are underestimated, and several species are extinct and in the endangered list. Objective: The aim of this review article is to draw the attention of common people and scientists toward a few important contributions of the aquatic plants to natural product chemistry and drug discovery by highlighting the chemical and pharmaceutical aspects of the same. Methods: The presented data were collected and selected from the literature obtained by an online search for the ethnomedicinal properties, biological activities and bioactive chemical constituents of aquatic plants using Google Scholar, PubMed and Scifinder chemical abstract service. Results: The selected literature data revealed that the extract and compounds isolated from several aquatic plants possess significant biological/pharmaceutical properties. For example, the α-asarone (24) and asiatic acid (33) isolated from Acorus calamus and Centella asiatica, respectively, exhibited significant neuroprotective effects in vitro and in vivo. The cripowellin A (59), cripowellin C (60), cripowellin B (61) and cripowellin D (62), isolated from Crinum erubescens, exhibited potent antiplasmodial and antiproliferative activities with half maximal inhibitory concentration (IC50) in nanomolar range (11-260 nM). Several other alkaloids from different Crinum species have also shown anticancer properties against different cancer cell lines with IC50 value <5 μM. Alkaloids and resin glycosides, isolated from different Ipomoea species, have displayed significant psychotropic, psychotomimetic, anticancer, and antibacterial activities with IC50 value <5 μM. Conclusion: The aquatic plants play a significant role in the discovery of bioactive natural products. Although several biological activities and bioactive compounds have been reported from these plants, further assessment and scientific validation of most of their traditional usages still need to be done. There are several other similar species that are underestimated and not much explored. Many aquatic plants, such as Ipomoea carnea Jacq., Juncus lomatophyllus Spreng., Commelina benghalensis Linn, Gunnera perpensa L., Scirpus maritimus L. and Mentha longifolia (L.) L., may be considered for further evaluation. In addition to these, one should not undermine the potential of Crinum macowanii for COVID-19 pathogenesis, as its chemical constituent lycorine has shown significant SARS-CoV-2 inhibitory potential (EC50, 0.3 μM; SI >129). Furthermore, most rural communities are still using the wetland resources for their cultural, medicinal, economic, domestic, and agricultural needs. Hence, the conservation of aquatic plants and wetlands is an issue of great concern.

Traditional remedies have been used for generations to treat and maintain people's health and indigenous medicinal plants are an important part of this system, which, unlike western medicine, provide cures for practically all illnesses with no side effects. Ulcer is a chronic ailment that affects most of the world's population and has no absolute cure. An ulcer is the erosion of mucous lining in the gastrointestinal tract due to over secretion of HCl in the stomach, leading to inflammation and soreness. Consumption of highly spicy meals, an obese lifestyle, an unplanned diet, the use of excessive nonsteroidal anti-inflammatory medicines, smoking, stress, an irregular sleep cycle, and regular alcohol consumption are all possible causes of ulcers. Ayurvedic and traditional medicine practitioners employ a variety of indigenous medicinal plants to cure ulcers. This review covers a wide variety of medicinal plants that may work as anti-ulcer and deserve more investigation.

The rising statistics of antimicrobial resistance pose an alarming concern for the mankind. The extensive/injudicious use of antibiotics in the environment, animal husbandry, and health care have led to the alarming rise of infectious microbes developing resistance against conventional drugs. The use of phytotherapeutics defines an attractive approach to tackling drug-resistant microbes, attributed to their ability to target major antimicrobial resistance mechanisms, including efflux pumps, biofilms, and cell membranes, among others. In recent times, the discovery and bioprospection of plants for value-added metabolites have witnessed a tremendous upsurge, with several phytomolecules demonstrating bactericidal and drug-resistance reversal properties. However, several existing challenges, including their low concentration in plants, climatic variations, overutilization of plant resources, and deforestation, have limited the utilization of phytotherapeutics. Discussing the growing concern of drug-resistant microbes and antimicrobial resistance, the thematic article discusses the existing and emerging scenarios of antimicrobial resistance in microbes. In the post-antibiotic era, phytotherapeutics defines enormous potential to tackle the growing threat of antimicrobial resistance, addressed through genetic engineering of microbes/plant systems for enhanced antimicrobial production. The success stories of antimicrobials from medicinal plants, as exemplified by key examples, associated challenges, possible strategies, and prospects of antimicrobials in drug discovery, form the key underlying theme of the article.

Early mushrooms were categorized under functional food/ nutritional food. However, later on, an increasing number of scientific studies strongly support their role in disease prevention and suppression or remission of a diseased state. Mycotherapy of cancer, a new promising field, deals with anticancerogenic agents derived from mushrooms. Rich in nutritive value, undemanding cultivation conditions, and an army of health-promoting bioactive molecules, collectively make Pleurotus mushroom ideal for a researcher to investigate its anti-cancer potential. The present review is a literature survey via. electronic search by two database search engines: Science Direct and PubMed, on the anti-cancer potential of Pleurotus species till 2021. This data profiling will -track information regarding the in vitro and in vivo anti-cancer activity of different Pleurotus species, along with identifying the bioactive molecules responsible for anti-cancer potential with their underlying mechanism of action. Resultant findings from the electronic search revealed that till 2021, nearly 13 species of Pleurotus mushroom had been studied for anti-cancer potential. The biomarkers responsible for activity are mostly higher molecular weight molecules, comprising polysaccharides, polypeptides, proteins, lectins, and enzymes. The lower molecular weight molecules like terpenoids, sterols, and phenolic compounds are less explored and untapped. The main underlying mechanism for the anticancer activity of Pleurotus mushrooms is the induction of the mitochondria intrinsic pathway. For anticancer, Pleurotus mushrooms are widely formulated as metal nanoparticles. Altogether, this detailed insight may give the researcher a path to be addressed, thus driving mass attention to identifying novel,effective, and safer anticancer potential biomarkers.

Background: The prevalence of cardiovascular diseases is being increased; researchers are trying to explore effective preventive and treatment options. Antioxidant effects and Angiotensin- Converting. Enzyme (ACE) inhibitors demonstrated cardioprotective effects. Many herbs and plants have shown antiinflammatory, antioxidant, free radical scavenging, and ACE inhibition properties in preventing and treating cardiac-related disorders. Therefore, the exploration of bioactive compounds such as polyphenols, flavonoids, quercetin, kaempferol, isoflavones, and catechin needs to be explored as potential ACE inhibitors and antioxidants in preventing and treating cardiac-related diseases. Objective: The present study is designed to investigate the cardio-protective potential of important bioactive compounds from plants and herbs. Methods: Articles were collected from electronic databases, such as PubMed, Google Scholar, Web of Science, and Science Direct, using the keywords antioxidant, anti-inflammatory, ACE inhibition and antihypertensive properties of plants and herbs. In vitro and in vivo studies on animal models have been included in the current study. Articles published in languages other than the English language were excluded, and finally, 100 manuscripts were included in this study. Results: Plants and herbs chosen for this study with abundant natural bioactive compounds have demonstrated ACE inhibition, antioxidant, anti-inflammatory, and anti-hypertensive properties and can be an effective cardioprotective. Hence, it could pave the way for the development of new therapeutics that could be beneficial in treating cardiovascular diseases. Conclusion: The current review focuses on herbs and plants possessing ACE inhibition, antioxidant, antioxidative, anti-inflammatory, hyperaccumulating and anti-hypertensive properties with their ability to prevent the breakdown of ACE I enzyme into ACE enzyme II, acting as ACE inhibitors and showing its strong potential as a cardioprotective agent. Also, it could support the development of new therapeutic agents to address cardiovascular problems.

Background: Ursolic acid (UA, 3β-hydroxy-urs-12-en-28-oic acid), a pentacyclic triterpenoid from various medicinal plants, has been blessed with proven biological effects, including antiinflammatory, anticancer, antidiabetic, antioxidant and antibacterial, but its bioavailability and solubility limit its clinical application. Objective: Synthesis of UA-based hybrid molecules to explore their antibacterial and synergy potential in combination with azithromycin (AZT) for the treatment of multidrug-resistant (MDR) bacterial infections. Methods: Hybrid molecules of UA with menthol, eugenol, and nalidixic acid (NAL) along with some other ester derivatives were synthesized, and evaluated for their antibacterial and synergy potential in combination with AZT against the clinical isolate of Escherichia coli in terms of their minimum inhibitory concentration (MIC), fold reduction in MIC, fractional inhibitory concentration index (FICI) and type of interaction. In silico screening of pharmacokinetic parameters, docking affinity against efflux pump proteins AcrA, AcrB, and TolC was performed on the most potent derivative 7 (3-O-nalidixoyl UA). Results: Derivative 7 showed MIC of 62.5 μg/mL and a strong synergistic effect with AZT reducing the MIC of AZT from 100 to 0.19 μg/mL (512-fold reduction) against E. coli at a concentration of 12.5 μg/mL. Other derivatives neither showed antibacterial activity of their own (MIC > 1000 μg/mL) nor any significant synergistic interaction in combination with AZT. The in silico studies on 7 revealed improved druggability parameters over the parent UA and NAL. Conclusion: The findings highlight derivative 7 as strong synergistic agent in combination with AZT which may be further investigated to render its efficient use for the treatment of MDR bacterial infections.

Background: Glycyrrhetinic acid (GA) is a biologically active triterpenoid acid, isolated from the root of the Glycyrrhiza plant species. In our earlier studies, the semisynthetic analogs of GA have been reported to possess improved anticancer activities against various cell lines, antimalarial, and antifilarial activities. Objective: Synthesis of novel C-3 aryl ester derivatives and evaluation of antitubercular activity in order to study structure activity relationship (SAR). Methods: GA was isolated and characterized from roots of Glycyrrhiza glabra and converted to its various C-3 aryl ester derivatives via the protection of C-30 carboxylic group. Antitubercular activity was determined against Mycobacterium tuberculosis H37Ra by Agar dilution assay. The in silico docking was performed for the most active analogue against three antitubercular targets, catalase peroxidase, dihydrofolate reductase and enoyl-ACP reductase. Results: The derivatives, Methyl glycyrrhetinate (GA-1), 3-O-(4-methyl-phenyl)-ethanoyl methyl glycyrrhetinate (GA-1a), 3-O-(4-fluoro phenyl)-ethanoyl methyl glycyrrhetinate (GA-1c), 3-O-(4-methoxy trans cinnamyl)-ethanoyl methyl glycyrrhetinate (GA-1e) and 3-O-{(4-chlorophenyl)-ethanoyl methyl glycyrrhetinate (GA-1g) showed improved antitubercular activity (in the range 38.76 to 51.546 mM) over the parent molecule (MIC >106.157 mM). The derivative, 3-O-(4-aminobenzoyl)- methyl glycyrrhetinate (GA-1h) was found most active (MIC 20.695 mM), which was further supported by high binding affinity with the selected antitubercular target proteins in in silico docking studies. Conclusion: Synthetic modifications on GA led to C-3 aryl ester derivatives with improved antitubercular activities. Further studies for the development of GA-1h as potential antitubercular lead is therefore warranted.

Background: The drugs available for the treatment of Chagas disease are ineffective in its chronic phase and produce many adverse effects, making the search for new drugs an urgent medical need. Objective: This study aimed to design, synthesize, and evaluate the trypanocidal and cytotoxic profiles of new 4-nitroimidazole prototypes. Methods: The new compounds were synthesized in overall yields ranging from 31-to 52% through the use of classical and reproducible methodologies. Their trypanocidal profile and cytotoxicity were assayed against trypomastigote forms of T. cruzi and mammalian macrophages, respectively. Results: The best trypanocidal activity was evidenced in compounds that present lipophilic and electronegative substituents, e.g. 4-chlorophenyl derivative (5), with an IC50 = 206.98 μM; Conclusion: The new benznidazole N-glycinyl-hydrazone analogues demonstrated a very significant reduction in the trypanocidal activity compared to benznidazole, which seems to be related to the position occupied by the nitro group in the imidazole ring.