1,3,4-thiadiazole is a five-membered aromatic heterocycle containing two nitrogen atoms and one sulfur atom. As a privileged scaffold, it has its unique chemical properties and biological ...characteristics. In the design of drugs, they are widely and flexibly applied by medicinal chemists, and many candidates with therapeutic prospects have been developed. In this review, we focus on 1,3,4-thiadiazole derivatives and their various biological activities reported in the past five years (from 2015 to early 2020), such as anticancer, antibacterial, antifungal, anti-tuberculosis, anti-inflammatory, antivirus, anti-leishmania and other functions. It is believed that this review can provide some new ideas for seeking rational design to develop 1,3,4-thiadiazole based medicinal agents with better activity and lower toxicity.
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A novel spirocyclic scaffold of 7'H-spiroazetidine-3,5'-furo3,4-dpyrimidine chemotype was synthesized in N-Boc-protected form. However, the scaffold was revealed to be unstable to ...storage when deprotected. The solution was found in the brief removal of the Boc protecting group and rapid acylation of the liberated NH-azetidine with a carboxylic acid imidazolide.
Rhodanines, thiazolidine-2,4-diones and pseudothiohydantoins have become a very interesting class of heterocyclic compounds since the introduction of various glitazones and epalrestat into clinical ...use for the treatment of type II diabetes mellitus and diabetic complications, respectively. Chemical modifications of these heterocycles constantly result in compounds with a wide spectrum of pharmacological activities. 5-Arylidenerhodanines are frequently identified as potent hits in high throughput screening against various prokaryotic and eukaryotic targets. Synthesis of substituted rhodanines, based on high throughput screening hits, often leads to potent and selective modulators of targeted enzymes or receptors, which exert their pharmacological activities through different mechanisms of action. Due to various possibilities of chemical derivatization of the rhodanine ring, rhodanine-based compounds will probably remain a privileged scaffold in drug discovery. We have therefore reviewed their biological activities, mechanism of action, structure activity relationship and selectivity against other targets.
The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing ...and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.
The current work presents an objective overview of the impact of one important heterocyclic structure, the pyrazole ring, in the development of anti-proliferative drugs. A set of 1551 pyrazole ...derivatives were extracted from the National Cancer Institute (NCI) database, together with their growth inhibition effects (GI%) on the NCI's panel of 60 cancer cell lines. The structures of these derivatives were analyzed based on the compounds' averages of GI% values across NCI-60 cell lines and the averages of the values for the outlier cells. The distribution and the architecture of the Bemis-Murcko skeletons were analyzed, highlighting the impact of certain scaffold structures on the anti-proliferative effect's potency and selectivity. The drug-likeness, chemical reactivity and promiscuity risks of the compounds were predicted using AMDETlab. The pyrazole ring proved to be a versatile scaffold for the design of anticancer drugs if properly substituted and if connected with other cyclic structures. The 1,3-diphenyl-pyrazole emerged as a useful scaffold for potent and targeted anticancer candidates.
Current therapy against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are based on the use of Remdesivir
, Molnupiravir
, and the recently identified Nirmatrelvir
. Unfortunately, ...these three drugs showed some limitations regarding potency and possible drug-drug interactions. A series of derivatives coming from a decoration approach of the privileged scaffold s-triazines were synthesized and evaluated against SAR-CoV-2. One derivative emerged as the hit of the series for its micromolar antiviral activity and low cytotoxicity. Mode of action and pharmacokinetic in vitro preliminary studies further confirm the role as candidates for a future optimization campaign of the most active derivative identified with this work.
s-triazine nucleus with various therapeutic applications.
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This article summarizes the most recent advancements in the synthetic and pharmacological approaches along with the structure ...activity relationship towards the s-triazine and its derivatives. Much attention has been given to s-triazine core due to its facile synthesis, interesting pharmacology, high reactivity, and binding characteristics towards various enzymes. An array of biological applications has been demonstrated by s-triazines including antimalarial, anti-HIV, anti-viral, antimicrobial, anti-tuberculosis to name a few. In the present investigation s-triazine based molecular structures have been assembled in respect to their synthesis and medicinal properties. Further, the competence of s-triazine has been correlated and compared with the other heterocyclic moieties to substantiates-triazine a privileged scaffold. From the literature it is revealed that nucleophilic substitution at 2, 4, and 6 positions is significant for various biological applications. This article would help in assisting the chemists in designing novel molecular entities with high medicinal value.
The term "privileged scaffold" was coined in 1988 and the strategy was to construct high-affinity ligands from core structures that can bind more than one receptor. Since then, the privileged ...scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms.
In this review, the authors discuss the applications of the privileged scaffold concept in current lead generation. Specifically, the authors cover the role that privileged scaffolds have played in the mass production of compounds to feed high-throughput screening (HTS) and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands. It is not the intention of the authors to review all privileged scaffolds known to date. Rather, the aim of this review is to highlight the strategic value of the concept of privileged scaffolds in various contemporary lead generation platforms.
The privileged scaffolds as described by the original definition proved abundant in the available chemical space. HTS and other screening methods, in addition to greatly enhanced compound collections, make privileged scaffold-based design less relevant in finding high-affinity ligands than originally envisioned. However, the principle of privileged scaffolds has greatly enhanced and empowered current lead generation technologies.
With the rapid development of computer science in scopes of theory, software, and hardware, artificial intelligence (mainly in form of machine learning and more complex deep learning) combined with ...advanced cheminformatics is playing an increasingly important role in drug discovery process. This development has also facilitated privileged scaffold-related research. By definition, a privileged scaffold is a structure that frequently occurs in diverse bioactive molecules, either has a diverse family affinity or is selective to multiple family members in a superfamily, whilst it is different from the"frequent hitters", or the "pan-assay interference compounds". The long history of the use of this concept has witnessed a functional shift from stand-alone technology towards an integrated component in the drug discovery toolbox. Meanwhile, continuous efforts have been dedicated to deepening the understandings of the features of known privileged scaffolds. In this contribution, we focus on the current privileged scaffold-related research driven by state-of-art artificial intelligence approaches and cheminformatics. Representative cases with an emphasis on distinct research aspects are presented, including an update of the knowledge on privileged scaffolds, proofof- concept tools, and workflows to identify privileged scaffolds and to carry on de novo design, informatic SAR models with diversely complex data sets to provide an instructive prediction on new potential molecules bearing privileged scaffolds.
Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially ...those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.
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