Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets.

Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer's, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC50 = 17.67 ± 0.89 µM), with a 4-fold increased activity relative to the standard drug indomethacin (IC50 = 67.16 ± 0.17 µM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.

Diastereoselective Synthesis of Fused Tricyclic Pyridopyrimidines via Tandem Cyclization of Allenoates and Cyclic Amidines.

The tandem cyclization of easily accessible allenoates and cyclic amidines for the synthesis of functionalized tricyclic pyridopyrimidines is reported herein. The annulation featured a broad substrate scope with good functional group tolerance under very mild conditions (35 examples, 32-85% yields). The pyridopyrimidines were obtained in a very short reaction time (1 min), at room temperature, under neat conditions, which offers an alternative way to the sustainable synthesis of functionalized pyridopyrimidines. The scalability of the developed protocol is further demonstrated by a gram-scale synthesis.

DBU-Catalyzed Diastereo/Regioselective Access to Highly Substituted Spiro-oxetane Oxindoles via Ring Annulation of Isatins and Allenoates.

A facile and efficient method for the diastereo/regioselective synthesis of highly functionalized spiro-oxetane oxindoles has been described. The 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed reaction proceeds via spiro-annulation of isatins and allenoates. The reaction is compatible with a wide range of isatins containing electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) with various allenoates affording the corresponding products in acceptable yields. It is noteworthy that this is the first protocol for constructing structurally diverse motifs of highly functionalized spiro-oxetane oxindoles of pharmaceutical relevance.

Ethnobotanical significance of medicinal plants: Beta-amyloid and tau aggregation inhibitors against Alzheimer's disease.

Among the various neurodegenerative disorders, Alzheimer's disease (AD) is identified as one of primary causes of dementia in the elderly, which progresses slowly leading to cognitive decline and ability to function independently. Although various pathological mechanisms have been proposed, the exact mechanism is not yet elucidated. Numerous processes such as old age, mitochondrial dysfunction, and genetics lead to the aggregation of beta-amyloid (Aß) as amyloid plaques and tau proteins as neurofibrillary tangles in the neurons leading to their death and destruction, finally leading to AD. The current treatment measures can only temporarily improve the symptoms, slowing cognitive decline without any effect on AD pathology for better therapeutic effect. Furthermore, the high failure rates of a number of drugs during clinical trials due to their side effects has led the researchers to focus on alternative sources for drug development. As natural ingredients were considered the primary line of treatment in the olden days, and as several medicinal plant products are also proven as effective AD targets, it will be wise to investigate those with significant ethnobotanical value as potential neuroprotectives, nootropics or memory boosters. Throughout the study, propanoids, glycosides, iridoids, carotenoids and flavonoids that show potential anti-inflammatory, antioxidant, and anti-cholinesterase were also found to be inhibitors of Aß and tau aggregation, where Saikosaponin C, Fisetin, and Morin can act as dual inhibitors. The review provides an insight in the need for proper and complete scientific evaluation of these ethnobotanically useful medicinal plants to be identified as potential leads in AD therapy.

Antibacterial natural products from microbial and fungal sources: a decade of advances.

Throughout the ages the world has witnessed the outbreak of many infectious diseases. Emerging microbial diseases pose a serious threat to public health. Increasing resistance of microorganisms towards the existing drugs makes them ineffective. In fact, anti-microbial resistance is declared as one of the top public health threats by WHO. Hence, there is an urge for the discovery of novel antimicrobial drugs to combat with this challenge. Structural diversity and unique pharmacological effects make natural products a prime source of novel drugs. Staggeringly, in spite of its extensive biodiversity, a prominent portion of microorganism species remains unexplored for the identification of bioactives. Microorganisms are a predominant source of new chemical entities and there are remarkable number of antimicrobial drugs developed from it. In this review, we discuss the contributions of microorganism based natural products as effective antibacterial agents, studied during the period of 2010-2020. The review encompasses over 140 structures which are either natural products or semi-synthetic derivatives of microbial natural products. 65 of them are identified as newly discovered natural products. All the compounds discussed herein, have exhibited promising efficacy against various bacterial strains.

Investigation of embelin synthetic hybrids as potential COVID-19 and COX inhibitors: Synthesis, spectral analysis, DFT calculations and molecular docking studies.

Embelin (2, 5-dihydroxy-3-undecyl-1,4-benzoquinone), a benzoquinone isolated from fruits of Embelia ribes has miscellaneous biological potentials including; anticancer, anti-inflammation, antibiotic, and anti-hyperglycemic activities. Also, embelin down-regulates the overexpression of inflammatory pathways like NF-kB, TACE, TNF-α, and other cytokines. Furthermore, embelin fascinated synthetic interest as a pharmacologically active compound. The present article involves the design, synthesis, DFT calculations, and molecular docking studies of embelin derivatives as cyclooxygenase inhibitors of embelin derivatives. The structure of these derivatives is confirmed by the various spectral analyses such as IR, NMR, and Mass. The DFT calculations were carried out for the molecules (1-8) using CAM-B3LYP hybrid functional with a 6-31+g(d) all-electron basis set using the Gaussian 09 package. Second-order harmonic vibrational calculations are used to check the minimum nature of the geometry. Further, HOMO and LUMO analyses were used for the charge transfer interface between the structures. Based on our previous work and structural activity relationship study, foresaid embelin derivatives were evaluated for in vitro COX-1 and COX-2 inhibitory activity. The compounds 3, 4, 7, and 8 demonstrated excellent COX inhibitions with IC50 values of 1.65, 1.54, 1.56, and 1.23 µM compared to standard drugs Celecoxib and Ibuprofen. Finally, the molecular docking studies carried out with Covid-19 and cyclooxygenase with all the newly synthesized embelin derivatives.

Multicomponent Synthesis of Spiro-dihydropyridine Oxindoles via Cascade Spiro-cyclization of Knoevenagel/Aza-Michael Adducts.

An efficient, straightforward, and one-pot synthesis of biologically relevant spiro-dihydropyridine oxindoles was described via readily available isatin, malononitrile, allenoate, and amines. The metal/organocatalyst-free, Et3N-mediated reaction proceeds via cascade spiro-cyclization of in situ generated Knoevenagel/aza-Michael adducts. The reaction has great flexibility over electron-rich and electron-poor substituents affording desired products in good to excellent yields. We have also demonstrated the selected spiro-dihydropyridines for late-stage diversification into new spiro-dihydropyridine hybrids of pharmaceutical relevance.

Comprehensive Review on Medicinal Applications of Coumarin-Derived Imine-Metal Complexes.

Coumarins are fused six-membered oxygen-containing benzoheterocycles that join two synthetically useful rings: α-pyrone and benzene. A survey of the literature shows that coumarins and their metal complexes have received great interest from synthetic chemists, medicinal scientists, and pharmacists due to their wide spectrum of biological applications. For instance, coumarin and its derivatives have been used as precursors to prepare a large variety of medicinal agents. Likewise, coumarin-derived imine-metal complexes have been found to display a variety of therapeutic applications, such as antibacterial, antifungal, anticancer, antioxidant, anthelmintic, pesticidal, and nematocidal activities. This review highlights the current synthetic methodologies and known bioactivities of coumarin-derived imine-metal complexes that make this molecule a more attractive scaffold for the discovery of newer drugs.

Marine Based Natural Products: Exploring the Recent Developments in the Identification of Antimicrobial Agents.

The marine ecosystem is the less explored, biologically diverse, and vastest resource to discover novel antimicrobial agents. In recent decades' antimicrobial drugs are losing their effectiveness due to the growing resistance among pathogens, which causes diseases to have considerable death rates across the globe. Therefore, there is a need for the discovery of new antibacterials that can reach the market. There is a gradual growth of compounds from marine sources which are entering the clinical trials. Thus, the prominence of marine natural products in the field of drug design and discovery across the academia and pharmaceutical industry is gaining attention. Herein, the present review covers nearly 200 marine based antimicrobial agents of 11 structural classes discovered from the year 2010 to 2022. All the discussed compounds have exhibited medium to high antimicrobial activity in inhibiting various microorganisms.

An insight into the recent developments in anti-infective potential of indole and associated hybrids.

Prevention, accurate diagnosis, and effective treatment of infections are the main challenges in the overall management of infectious diseases. The best example is the ongoing SARs-COV-2(COVID-19) pandemic; the entire world is extremely worried about at present. Interestingly, heterocyclic moieties provide an ideal scaffold on which suitable pharmacophores can be designed to construct novel drugs. Indoles are amongst the most essential class of heteroaromatics in medicinal chemistry, which are ubiquitous across natural sources. The aforesaid derivatives have become invaluable scaffolds because of their wide spectrum therapeutic applications. Therefore, many researchers are focused on the design and synthesis of indole and associated hybrids of biological relevance. Hence, in the present review, we concisely discuss the indole containing natural sources, marketed drugs, clinical candidates, and their biological activities like antibacterial, antifungal, anti-TB, antiviral, antimalarial, and anti-leishmanial activities. The structure-activity relationships study of indole derivatives is also presented for a better understanding of the identified structures. The literature data presented for the anti-infective agents herein covers largely for the last twelve years.

Anti-hyperlipidemic potential of natural product based labdane-pyrroles via inhibition of cholesterol and triglycerides synthesis.

Hyperlipidemia is the clinical condition where blood has an increased level of lipids, such as cholesterol and triglycerides. Therefore controlling hyperlipidemia is considered to be a protective strategy to treat many associated diseases. Thus, a novel natural product derived pyrrole, and pyrazole-(E)-Labda-8(17),12-diene-15,16-dial conjugates with cholesterol and triglycerides synthesis inhibition potential was designed through scaffold hopping approach and synthesized via one-pot selective cycloaddition. Amongst the tested hybrids, 3i exhibited excellent activity against triglyceride and cholesterol synthesis with the percentage inhibition of 71.73 ± 0.78 and 68.61 ± 1.19, which is comparable to the positive controls fenofibrate and atorvastatin, respectively. Compounds 3j and 3k also exhibited the considerable potential of promising leads. The HMG CoA reductase inhibitory activity of the compounds was consistent with that of inhibitory activity of cholesterol synthesis. Compound 3i showed the highest inhibitory potential (78.61 ± 2.80) percentage of suppression, which was comparable to that of the positive control pravastatin (78.05 ± 5.4). Favourably, none of the compounds showed cytotoxicity (HepG2) in the concentration ranging from 0.5 to 100 µM.

Base-enabled access to diastereoselective spirofuran oxindoles and γ-functionalized allenoates.

Base assisted divergent reactivity of isatins and allenoates has been achieved, which afforded diastereoselective spirofuran oxindoles and γ-functionalized allenoates. The DBU mediated Morita-Baylis-Hillman (MBH) reaction followed by the cascade annulation through the stabilized ß-ammonium enolate intermediate led to the spiro-framework, wherein DABCO furnished the γ-functionalized allenoates. The protocol offers access to biologically relevant functionalized oxindole scaffolds with an excellent substrate scope under mild reaction conditions.

Advanced glycation end-products (AGE) trapping agents: Design and synthesis of nature inspired indeno[2,1-c]pyridinones.

Advanced glycation end products (AGEs) are implicated to be the key players in most of the diabetic complications. The AGE's interfere with the proteins heterogeneously, thereby rendering denaturation and the consequent loss of function and accumulation. Thus, a novel natural product inspired indeno[2,1-c]pyridinone (4a-4ad) molecular templates with AGE's trapping potential was designed through scaffold hopping approach and synthesized via facile two-step synthetic route. Amongst the tested indeno[2,1-c]pyridinone hybrids, 4i, 4x and 4aa exhibited excellent efficiency in trapping the AGE's. The percentage of antiglycation is measured by the analytical model system, i.e. via MG trapping capacity; here the compounds 4i, 4x and 4aa with 50.03%, 69.58%, and 93.37% respectively has displayed promising efficiency. In particular, 4aa demonstrated better activity than the positive control aminoguanidine (79.82%). The in-vitro toxicity of compounds was tested on L6 rat skeletal muscle cell lines revealed that none of the compounds showed any significant toxicity at concentrations up to 1000 µM.

Rapid Visual Detection of Amines by Pyrylium Salts for Food Spoilage Taggant.

Amines are ubiquitous in biological world, but are toxic and harmful in nature. Detection of biogenic amines that are released from spoiled seafood, meat, or dairy products is an important task to maintain the quality and safety of these packaged foods. To this endeavor, herein we report pyrylium salts that are capable of sensing various amines by rapid change of fluorescence color or intensity. In molecular level, this change of fluorescence is rooted to the formation of pyridine or analogous product that have distinct optical property. The pyrylium salts are capable of efficiently sensing amine vapors or amine solutions both in solid state and in solution state and thus demonstrating a multiphase sensing platform. Utilizing the excellent sensing property, we have employed our pyrylium compounds as spoilage indicator for food products such as fish, meat or cheese which relies on sensing biogenic amines released from these spoiled foods and provide optical response. Prominent change in visible and luminescence color was observed within 4-18 h of packaging at room temperature (∼33 °C). Considering the rapid response for biogenic amines, these molecular sensors have great potential to be utilized for food packaging industry, medical diagnostics, or other sensory devices.

Discovery of Natural Product Derived Labdane Appended Triazoles as Potent Pancreatic Lipase Inhibitors.

Obesity contributes to the genesis of many metabolic disorders including dyslipidemia, coronary heart disease (CHD), nonalcoholic fatty liver, type 2 diabetes, etc. Pancreatic lipase plays a vital role in food fat digestion and absorption. Therefore, to control obesity, inhibition of pancreatic lipase is the active therapy. Thus, novel natural product derived labdane appended triazoles with pancreatic lipase inhibition potential were designed and synthesized. Among these hybrids, 6b and 6f exhibited excellent inhibitory activity (IC50 0.75 ± 0.02 µM and 0.77 ± 0.01 µM), slightly better than that of the positive control Orlistat (IC50 0.8 ± 0.03 µM). Compounds 6c, 6e, and 6g-j inhibited the PL comparable to that of positive control. Interestingly none of the compounds showed cytotoxicity (Hep G2) in the concentration range from 0.5 to 100 µM. Overall results reveal the potential of labdane appended triazoles as antiobesity agents.

Synthesis of 1,2,4-Trisubstituted-(1H)-imidazoles through Cu(OTf)2-/I2-Catalyzed C-C Bond Cleavage of Chalcones and Benzylamines.

1,2,4-Trisubstituted-(1H)-imidazoles have been synthesized by the Cu(OTf)2- and I2-catalyzed unusual C-C bond cleavage of chalcones and benzylamines. After the α,ß-unsaturated C-C bond cleavage, the ß-portion is eliminated from the reaction. Various aryl- and heteroaryl-substituted chalcones and benzylamines were well tolerated in this unusual transformation to yield the trisubstituted-(1H)-imidazoles.