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Examples of natural products (NP) as sources of drugs (blue rectangle) and NP-inspiring compounds (green rectangle).
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Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp³-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural divers...
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... examples of NPs as sources of drugs are shown in Figure 1. Acetylsalicylic acid (Aspirin): an anti- inflammatory agent derived from salicin, which is isolated from the bark of the willow tree Salix alba L; (Dias, Urban, Roessner, 2012) dopamine: a neurotransmitter obtained from phenylethylisoquinoline alkaloid by hydroxylation of tyrosine to L-3,4-dihydroxyphenylalanine (DOPA) followed by decarboxylation; solifenacin used to treat overactive bladder is derived from tetrahydroisoquinoline and has additional functional groups on this ring; ...
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... two types of NP-based drugs (NPD and PUNP) given in Figure 1, provide new opportunities to enhance the application of alternative strategies for drug discovery. ...
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... approach tends to generate simpler compounds, however, without escaping from the properties of NP scaffolds, making structural diversity one of the most important features of FBDD. (Over et al., 2012). The development of fragment library based on NP structures can be oriented according to research interest and library features. ...
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... it is possible to generate new fragments by in silico degradation. In this case, in silico reactions are applied to specific structures to generate a virtual products library ( Figure 10) (Prescher et al., 2017). In these two approaches, target fragments are generated from a NP-guided compound library development approach and can be selected for chemical elaboration according to biology results. ...
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... DOS can provide access to complex and diverse small molecules, thereby demonstrating great promise in modulating the activity of many targets that have largely been outside the purview of traditional compound collections (Dandapani, Marcaurelle, 2010). In addition, DOS is of great significance in both chemical and pharmaceutical fields (Wetzel et al., 2011). ...
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... example of indole-containing NP is Yohimbine (Figure 11), which has a highly complex ring system fused to an indole nucleus (Paciaroni et al., 2017). However, the development of novel DOS and BIOS approaches remains a challenging task, demanding more efficient protocols for the production of heterocycles ( Liu et al., 2018). ...
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... d e m o n s t r a t e r i n g -d i s t o r t i o n s t r a t e g y, (Figure 11-14) four of the most readily available and well-studied NPs were selected, including the alkaloids Yohimbine and quinine, the diterpene gibberellic acid, and the steroid adrenosterone. ...
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... develop an innovative strategy, the ring-distortion methodology involving Yohimbine as a platform was used to generate complex and diverse small molecules with unique and diverse molecular architectures (Paciaroni et al., 2017). Figure 11 shows a tryptoline ring-distortion strategy that enabled the rapid synthesis of four complex and diverse compounds (A-D) from Yohimbine ( Paciaroni et al., 2017). ...
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... stereochemical complexity, diverse functionality (a tertiary amine, a secondary alcohol, an olefin, and a quinoline), and two discrete ring systems of quinine (Figure 12), (Huigens et al., 2013) make it amenable to selective ring-system distortion to produce diverse molecular scaffolds. ...
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... diterpene gibberellic acid enables the selective and independent functionalization ( Figure 13) of each ring of the core structure via various reactions that can distort the tetracyclic diterpene core with a fused lactone (Huigens et al., 2013;Hergenrother et al., 2013). ...
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... the known chemical reactivity of these functional groups, two-or three-step reactions can be employed to convert adrenosterone into four structures (Figure 14, M-P). Applying a novel Schmidt reaction and synthetic elaboration (catalyzed by DMAP) yielded M and N. Oxidative cleavage of adrenosterone ring using NaIO 4 and KMnO 4 and further elaboration using Baeyer- Villiger rearrangement or Schmidt reaction yielded O and P (Huigens et al., 2013). ...
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... expansion is an efficient method to form novel ring skeletons or as a prelude to ring-cleavage reactions as shown in Figure 14. Changing the molecular volume and shape can be useful in controlling the lipophilicity of small molecules for use as drugs, and as an initial point for the design of compounds inherently biased by biological success. ...
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... Phenotypic screening campaigns have long been crucial to the identification of biologically active small molecules in conjunction with target-based approaches [1,2]. Because of their biological relevancy and favorable physicochemical properties, novel scaffolds from nature are frequently used to inspire the preparation of compound collections for phenotypic screening [3][4][5][6]. Pyridoxine (1) is a form of vitamin B 6 that scavenges reactive oxygen species and regulates diverse cellular metabolisms, including amino acid biosynthesis and fatty acid biosynthesis ( Figure 1) [7][8][9][10][11]. Inspired by pyridoxin (1), our group has pursued derivative syntheses along with biological investigations to explore the pharmacological potential of the 6-aminopyridin-3-ol scaffold (2). ...
Described in this paper are studies on the preparation of three classes of dimethylpyridinols derived from pyridoxine fused with aminooxazole, aminoimidazole, and aminopyrrole. The key feature of this synthetic strategy is the manipulation of hydroxymethyl moiety of C(5)-position of the pyridoxine starting material along with the installation of an amino group at C(6)-position. Efficient and practical synthesis for the oxazole- and imidazole-fused targets was accomplished, while the instability of the pyrrole-fused one was observed.
... For the creation of the diversity of the NP library, many techniques have been used for decades that showed plants as the main source of 'new' natural compounds [17]. Recently, novel strategies have provided a rich collection of NP diversity because the recognition of new chemo-types for drug development is a crucial requirement in many therapeutic areas [16][17][18][19][20]. Different strategies like diversity-oriented synthesis (DOS), diverted total synthesis (DTS), Complexity-to-Diversity (CtD), fragment-based drug design (FBDD), etc., and associated methods have been reported to attain stability and feasibility of novel scaffolds [21][22][23][24]. ...
... .(19). Complexity-to-Diversity Strategy. ...
Natural products have stimulated chemists owing to their abundant structural diversity and complexity. Indeed, natural products have performed an essential role, particularly in the cure of cancerous and infectious diseases, thereby posing medicinal researchers with a scope of unexplored chemotypes for the innovation of new drugs. Fusion of chemical derivatization and combinatorial synthesis forms the basis of the concept of chemo diversification of plants. Diverse libraries of natural product analogs are constructed through existing biological and chemical approaches using unique schemes to expand natural product frameworks. This review aims to present several approaches employed to offer innovative opportunities to synthesize NP-inspired compound libraries. Reactive molecular fragments present in most natural products are chemically converted to chemically engineered extracts (CEEs) or semisynthetic compounds constituting distinct libraries. Bio-guided isolation for natural products required vital tools like reverse phase chromatography and bioautographic assays. Different established strategies from DTS, BIOS, CtD, FOS, FBDD to Late-stage diversification facilitate the expansion of molecules with physicochemical properties. In particular, fragment-like natural products with novel skeletons may be used as preliminary points for chemical biology and medicinal chemistry programs with great capacity. In this review, we sum up how NPs have proven fruitful for the novel methodologies responsible for the diversification of complex natural products; thereby, it is worthy of going over the upcoming integration of natural products with combinatorial chemistry.
... The great diversity of molecular targets and structural characteristics of natural compounds makes them the origin and development of new drugs, challenging organic chemists to develop innovative synthetic strategies inspired by the arsenal of natural products [1]. Total syntheses and chemical changes are the basis of research and development of innovative drugs obtained from chemically modified natural compounds with various functional groups that greatly improve their biological properties. ...
Diabetes as well as the enhanced microbial multidrug resistance resulting from biofilm formation, constitutes some of the major health problems around the world. Triterpenoids and their derivatives have been shown to have a great contribution in this domain. A small library of benzoyl esters of lupeol and β-amyrin was synthesized and their structures were characterized by electronic ionization mass spectrometry (EIMS). Their inhibitory potential on pathogenic bacteria biofilms, as well as their inhibitory action on α-amylase and β-glucosidase activities were evaluated. The mass fragmentation patterns from the EIMS data confirm the success of the reactions. The minimal inhibitory concentrations (MIC) varied from 250-1000 µg/mL in the antimicrobial activities. Biofilm inhibitory potential of the compounds on S. aureus, E. coli and C. albicans were performed at MIC and sub-MIC concentrations and the results showed concentration-dependent inhibition of biofilms. At MIC, the highest biofilm inhibition was exhibited by compound 7 on S. aureus (60.8±3.2%), compound 3 on E. coli (60.5±2.8%) and compound 8 on C. albicans (56.9±2.5%). For all tested compounds, percentage inhibition of violacein production was 100% at MIC except for the starting compounds 1 and 2. At 24.24 µg/mL the percentage of inhibition varied from 22.9±1.2% to 42.1±1.0% for α-amylase inhibition and at a concentration of 10 µg/mL the percentage of inhibition varied from 49.8±0.3% to 69.3±1.0% for β-glucosidase inhibition. The highest inhibition was shown by compounds 7 and 8 on α-amylase and β-glucosidase assays, respectively. The results show that introduction of benzoyl ester groups at C-3 of lupeol and β-amyrin considerably improves their antibiofilm and antidiabetic potentials.
... Certainly, these shreds of evidence demand the development of better therapeutic drugs with minimal side-effects. Natural products comprise of diverse chemical scaffolds and identified as an excellent source to possess drug-like properties for several disorders (Silva & Emery, 2018;Mann, 2002). Research in the direction of employing food essentials, such as flavonoids and stilbenoids marks a great virtue of exploration. ...
Peroxisome Proliferator-Activated Receptors-γ (PPAR-γ), a ligand-activated transcription factor, suggested having anti-inflammatory effects by activating the target genes when bound to the ligand. Herein, we examined a conformational analysis of 8708 derivatives of Kaempferol, Quercetin, and Resveratrol, the prime activators of PPAR-γ molecular target by employing molecular docking and dynamic simulation pipeline to screen out potential agonists. The structure-based docking procedure performed by FlexX tool shortlisted high binding affinities of these derivatives of Kaempferol, Quercetin and Resveratrol with the protein receptor with a score of −38.94 kcal/mol (4'-Carboxy-5, 7-Dihydroxyflavone-CDHF), −41.63 kcal/mol (Demethyltorosaflavone D- DMTF) and −31.52 kcal/mol (Resveratrol-O-disulphate- RD) respectively, signifying the selected derivatives forms interactions like H-bond, Aromatic H-Bond, Pi-Pi stacking and salt bridges with PPAR-γ. The PPAR-γ-derivative complex was stabilized by intermolecular hydrogen bonds and stacking interactions. A greater interaction was significantly observed between the binding affinities of derivatives compared to the standards. Based on the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) carried by the means of high-speed molecular dynamics (MD) and simulation of best-docked poses, the ligand, DMTF attained the most favored interaction with PPAR-γ. Thus, it appeared to have high chemical scaffold diversity and may confer high drug-likeness. The binding free energy (ΔG) led us to manifest Quercetin derivative to have a key role for PPAR-γ receptor. The result obtained clearly indicates the exploitation of the promising new drug leads that may further influence in synthesizing and analyzing the development as anti-cancer agonists.
Communicated by Ramaswamy H. Sarma
... -an increase in rigidity -a predominance of fused, bridged, and spiro ring systems NPs are structurally distinct [44] and hold a large number of sp 3 hybridized carbons, spiro, bridged connected systems and high structurally diverse stereogenic centers [45]. Earlier, structural rigidity had favorably correlated with successful clinical candidate translations, a property which depends on the NRB descriptor [46]. ...
The discovery of a drug is known to be quite cumbersome, both in terms of the microscopic fundamental research behind it and the industrial scale manufacturing process. A major concern in drug discovery is the acceleration of the process and cost reduction. The fact that clinical trials cannot be accelerated, therefore, emphasizes the need to accelerate the strategies for identifying lead compounds at an early stage. We, herein, focus on the definition of what would be regarded as a “drug-like” molecule and a “lead-like” one. In particular, “drug-likeness” is referred to as resemblance to existing drugs, whereas “lead-likeness” is characterized by the similarity with structural and physicochemical properties of a “lead”compound, i.e. a reference compound or a starting point for further drug development. It is now well known that a huge proportion of the drug discovery is inspired or derived from natural products (NPs), which have larger complexity as well as size when compared with synthetic compounds. Therefore, similar definitions of “drug-likeness” and “lead-likeness” cannot be applied for the NP-likeness. Rather, there is the dire need to define and explain NP-likeness in regard to chemical structure. An attempt has been made here to give an overview of the general concepts associated with NP discovery, and to provide the foundational basis for defining a molecule as a “drug”, a “lead” or a “natural compound.”
... -an increase in rigidity -a predominance of fused, bridged, and spiro ring systems NPs are structurally distinct [44] and hold a large number of sp 3 hybridized carbons, spiro, bridged connected systems and high structurally diverse stereogenic centers [45]. Earlier, structural rigidity had favorably correlated with successful clinical candidate translations, a property which depends on the NRB descriptor [46]. ...
The discovery of a drug is known to be quite cumbersome, both in terms of the microscopic fundamental research behind it and the industrial scale manufacturing process. A major concern in drug discovery is the acceleration of the process and cost reduction. The fact that clinical trials cannot be accelerated, therefore, emphasizes the need to accelerate the strategies for identifying lead compounds at an early stage. We, herein, focus on the definition of what would be regarded as a “drug-like” molecule and a “lead-like” one. In particular, “drug-likeness” is referred to as resemblance to existing drugs, whereas “lead-likeness” is characterized by the similarity with structural and physicochemical properties of a “lead”compound, i.e. a reference compound or a starting point for further drug development. It is now well known that a huge proportion of the drug discovery is inspired or derived from natural products (NPs), which have larger complexity as well as size when compared with synthetic compounds. Therefore, similar definitions of “drug-likeness” and “lead-likeness” cannot be applied for the NP-likeness. Rather, there is the dire need to define and explain NP-likeness in regard to chemical structure. An attempt has been made here to give an overview of the general concepts associated with NP discovery, and to provide the foundational basis for defining a molecule as a “drug”, a “lead” or a “natural compound.”
Through vicinal difunctionalization of nitriles, a successful, innovative strategy for the synthesis of N-alkyl amidines is developed. This methodology capitalizes on commercially available nitriles, alcohols, and sulfonamides. The activation of...
This study examines how two popular drug‐likeness concepts used in early development, Lipinski Rule of Five (Ro5) and Veber's Rules, possibly affected drug profiles of FDA approved drugs since 1997. Our findings suggest that when all criteria are applied, relevant compounds may be excluded, addressing the harmfulness of blindly employing these rules. Of all oral drugs in the period used for this analysis, around 66% conform to the RO5 and 85% to Veber’s Rules. Molecular Weight and calculated LogP showed low consistent values over time, apart from being the two least followed rules, challenging their relevance. On the other hand, hydrogen bond related rules and the number of rotatable bonds are amongst the most followed criteria and show exceptional consistency over time. Furthermore, our analysis indicates that topological polar surface area and total count of hydrogen bonds cannot be used as interchangeable parameters, contrary to the original proposal. This research enhances the comprehension of drug profiles that were FDA approved in the post‐Lipinski period. Medicinal chemists could utilize these heuristics as a limited guide to direct their exploration of the oral bioavailability chemical space, but they must also steer the wheel to break these rules and explore different regions when necessary.
