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Natural products have been extensively explored for their role in drug design and development to eradicate numerous types of diseases. Also, heterocycles‐based motifs are known to possess a wide range of therapeutic applications. Among them, pyrazole is a well‐exploited scaffold by researchers in the different fields of medicinal chemistry. Recently, pharmacophoric hybridization became most urged approach in which two biologically active pharmacophoric skeletons tend to fuse together in any structural portion. Hence, pyrazole and its cyclic bio‐isosteres may clubbed together to design and develop novel potent molecules against clinical disorders with least toxicity profile. In the present review, we aim to compile the numerous recent advancements in the medicinal chemistry of natural metabolites containing pyrazole and its bio‐isosteres hybrid compounds with the following objectives: (1) To summarize the recent literature reports of last six years that are focused on the biological potential of natural pyrazole and its bio‐isosteres hybrid derivatives; (2) To deliberate current developments in the medicinal aspect of natural compounds through their structural alteration by introducing pyrazole and its cyclic analogues; (3) To emphasize the complete correlation between structure activity relationship (SAR) and therapeutic response to disclose productive concepts for the generation of potential semi‐synthetic candidates. [ABSTRACT FROM AUTHOR]

The 4‐thiazolidinone moiety is a privileged scaffold showing diversity in biological responses like antiinflammatory, antidiabetic, anticancer, antitubercular, anesthetic, hypnotic, antiviral and many more. As a result of this, researchers have been studying and synthesizing this class of heterocycles through several simple as well as complex pathways as the target scaffold for biological studies. This review recapitulates the recent advances in the chemical and biological activities of 4‐thiazolidinones that have proved to be of immense importance in the discovery and development of several molecules and, thereby, the treatment of many ailments. This study will add to previously published reviews by examining the research on various biological activities of 4‐thiazolidinones, including patents, with a focus on structure–activity relationship (SAR) investigations. Literature and patents emphasizing synthetic schemes and biological activities of 4‐thiazolidinones have covered the data in the last decade. Here, sufficient efforts have been put into place to compile the synthetic strategies, establish SARs and enlist various patents so far for this fantastic molecule. The facile synthetic schemes and a vast range of biological activity profiles possessed by this nucleus may provide researchers with new opportunities toward novel therapeutics. [ABSTRACT FROM AUTHOR]

Cancer is a broad word for a set of diseases that can begin in virtually any organ or tissue of the body and spread to other organs. In 2020, cancer was the largest cause of death worldwide, accounting for 10 million fatalities, or one in every six deaths. Nitrogen containing heterocyclic compounds are a massive research focus because it has a unique position and is a cherished source of a wide range of bioactive molecules in medicinal chemistry. Over 75% of the currently accessible market is covered by FDA‐approved drugs containing nitrogen moieties. DNA topoisomerase II is a reassuring approach for novel anticancer heterocyclic medicines because it plays a crucial role in DNA metabolism, replication, recombination, and repair. Given the importance of topo II in chemotherapy, there is a pressing necessity to boost topo II or multi‐target topo II inhibitors in order to combat drug resistance and minimize toxicity. Following the trend of researching the advancement of effective topo II inhibitors with minimal toxicity, the current review article consolidates a detailed account of nitrogen‐containing heterocyclic compounds and categorizes them into different classes based on structural characterization, such pyrimidine, triazine, pyridine, quinazoline, fluoroquinolones, quinones, pyrazoles, quinoline, carbazoles, β‐carboline, quinolone, naphthalimide, acridone, benzoxazole, pyridophenoxazine, pyrrole, piperazine and imidazole, along with their structure activity relationship, mechanistic aspects, and docking studies (wherever appropriate) were explored. We are certain that the current review paper will help future medical researchers investigate prospective topoisomerase inhibitors as anticancer medicines in a variety of clinical settings. [ABSTRACT FROM AUTHOR]

Rhodanine or 2‐Thioxothiazolidin‐4‐one is a privileged heterocyclic compound offering a wide opportunity for structural modification, lead development, and modification. It is one of the highly decorated scaffolds in the drug discovery process. Rhodanine derivatives possess a plethora of biological activities due to their ability to interact with a diverse range of protein targets, which provide tremendous opportunities to discover new drugs with different modes of action. The most common strategy for developing novel rhodanine derivatives is the introduction of structurally diverse substituents at the C‐5 or N‐3, or both positions. Since the inception of Epralestat into the market in 1992, the exploration of rhodanine‐3‐acetic acids has led to the development of novel leads against different biological targets such as MRSA, HHV‐6, Mycobacterial tuberculosis, dengue, etc. In the current pandemic era, some rhodanine compounds have been explored against SARS‐CoV‐2. In recent years, rhodanine and its derivatives have witnessed significant progress in developing new drug leads as potential antimicrobial and antiviral agents. Different synthetic methodologies and recent developments in the medicinal chemistry of rhodanine derivatives, including biological activities, their mechanistic aspects, structure–activity relationships, and in silico findings, have been compiled in the present review. This article will benefit the scientific community and offer perspectives on how these scaffolds as privileged structures might be exploited in the future for rational design and discovery of rhodanine‐based bio‐active molecules. [ABSTRACT FROM AUTHOR]

Heterocyclic scaffolds are playing the important role in drug discovery and development. Currently many heterocyclic scaffolds like thiazole, thiazolidinone or thiazolidinedione have proved to be vital or provide life support against cancer and inflammation. The present work reports the ten 4-thiazolidinone derivatives synthesized via conventional route using three subsequent steps. The structural identification of the compounds was determined through spectrophotometric analysis. Further, the synthesized compounds were subjected to antioxidant, anti-inflammatory, and anticancer activities. All the synthesized derivatives possessed good to moderate antioxidant effects with maximum scavenging exhibited by FP7 and FP10. The in vivo anti-inflammatory activity was performed by the carrageenan-induced rat paw edema method and the compounds FP4 and FP7 possessed maximum inhibition. The synthesized analogs were subjected to in vitro antitumor activity over MOLT-4, EAC cell lines and it was found that compounds FP4, FP7, and FP10 emerged out as the most potent analogs against the tested cell lines. Molecular docking studies were carried out using Auto Dock 4.2.6 software. Structure-activity relationship gave a clear picture of title compounds such as electron-donating (OH, OCH3) groups at arylidene ring at position-5 increase antioxidant activity and is decreased by the presence of an electron-withdrawing group at the same position. Chloro substituted phenyl imino group at second position enhanced the anti-inflammatory activity while substituting electron-donating groups on arylidene moiety attached with fifth position of 4-thiazolidinone improved the anticancer activity. [ABSTRACT FROM AUTHOR]

The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR. [ABSTRACT FROM AUTHOR]

Heterocyclic rings have long piqued the interest of medicinal chemists. Quinazolinone is a fused nitrogen‐based heterocyclic moiety. Some of quinazolinone derivatives have emerged as marketed drugs. A tremendous number of pharmacological activities such as anticancer, anticonvulsant, antimalarial, antifungal, antibacterial, antiinflammatory, MMP inhibitors, antidiabetic, antileishmanial, and hypolipidemic properties have been explored. A number of quinazolinone derivatives have already paved way in various stages of clinical trials. An extensive literature on developed synthetic schemes based on green chemistry and biological activities of quinazolinone has been included in this study. The content of patent filed and granted of various quinazolinone‐based compounds are also mentioned. [ABSTRACT FROM AUTHOR]

The dihydrofolate reductase (DHFR) is a significant target in cancer, microbial infection, fungal infection, malaria, leishmaniasis, and tuberculosis, among other diseases. The DHFR gene was discovered in prokaryotes and eukaryotes in the late 1950s and is found in all dividing cells. DHFR inhibitors are used for a variety of medicinal purposes. Increased resistance to therapeutic agents such as anticancer, antibiotic, anti‐tuberculosis, and antifungal sparked interest in the development of potent, broad‐spectrum medicines to address the issues. DHFR is a critical target in the development of innovative solutions to address the issues. Methotrexate, trimethoprim, sulfonamides, pyrimethamine, aminopterin, methotrexate, edatrexate, and pralatrexate are only a few of the medications that target DHFR. These medications are known as DHFR inhibitors. These inhibitors block the enzyme dihydrofolate reductase, resulting in a folic acid synthesis pathway that is compromised. The DHFR is involved in the conversion of dihydrofolate to tetrahydrofolate. Purine, pyrazole, pyrimidine, triazole, oxadiazole, and other heterocyclic motifs have shown to have a potential effect on the DHFR. In the medicinal chemistry community, a better understanding of the so‐called enzyme and biochemical underpinnings responsible for enzyme selectivity has led to the development of improved, unique, and new treatments. Several researchers are working on DHFR inhibitors intensely, using a variety of synthetic techniques, molecular modelling, mechanistic studies, in‐vitro and in‐vivo biological evaluations, and structure‐activity relationships (SAR). This review, compiles the findings of several research groups during the last five years. The molecular biology of DHFR, its biosynthetic pathway, and the powerful structure of DFHR inhibitors discovered during the search are all included in this review. The study also includes the latest developments in synthetic methods, molecular docking, and structure‐activity relationships. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase is the tyrosine kinase encoded by an X chromosome gene, was first mutated in a boy with Bruton's disease, known as X-linked agammaglobulinemia. Bruton's tyrosine kinase (BTK) is essential for the survival of leukemic cells in a variety of B cell malignancies. It controls the development and function of B cells (also referred as B-lymphocytes). It is one of the many non-receptor Tec (tyrosine kinase expressed in hepatocellular carcinoma) protein tyrosine kinases. One emerging moiety with potential efficacy in B-cell malignancies is pyrimidines, inhibiting Bruton's tyrosine kinase (BTK). About 20 years passed from the time a target was discovered and the beginning of therapeutic research before the drug received approval. Ibrutinib, a first of its kind medicine, through which B-cell cancers can be treated without the need of chemotherapy. In order to better comprehend the clinical and commercial potential of pyrimidines as BTK inhibitors, as well as the directions being pursued, we have highlighted the important milestones in their preclinical discovery and clinical development in this review. Moreover, it provides important insights related to SAR studies that might be applied to the research and development of future innovative medicines. [Display omitted] • Bruton's tyrosine kinase as a crucial modulator of B-cell receptor signaling. • Pyrimidine scaffolds against Bruton's tyrosine kinase for the last six years. • Mechanistic approaches and structure activity relationship. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mitogen activated protein kinase (MAPK) signalling pathway represent the major target in the treatment of cancer. • Recent advancements in the medicinal chemistry of MAPK inhibitors along with detailed SAR have been described. • In silico , mechanistic studies, in vitro and in vivo studies have been discussed. • The present study helps scientist working in the field of oncology to develop novel MAPK signalling pathway inhibitors. The mitogen activated protein kinase (MAPK) belongs to group of kinase that links the extracellular stimuli to intracellular response. The MAPK signalling pathway (RAS-RAF-MEK-ERK) involved in different pathological conditions like cancer, caused due to genetic or any other factor such as physical or environmental. Many studies have been conducted on the pathological view of MAPK cascade and its associated element like RAS, RAF, MEK, ERK or its isoforms, and still the research is going on particularly with respect to its activation, regulation and inhibition. The MAPK signalling pathway has become the area of research to identify new target for the management of cancer. A number of heterocyclics are key to fight with the cancer associated with these enzymes thus give some hope in the management of cancer by inhibiting MAPK cascade. In the present article, we have focussed on MAPK signalling pathway and role of different heterocyclic scaffolds bearing nitrogen, sulphur and oxygen and about their potential to block MAPK signalling pathway. The heterocyclics are gaining importance due to high potency and selectivity with less off-target effects against different targets involved in the MAPK signalling pathway. We have tried to cover recent advancements in the MAPK signalling pathway inhibitors with an aim to get better understanding of the mechanism of action of the compounds. Several compounds in the preclinical and clinical studies have been thoroughly dealt with. In addition to the synthetic compounds, a significant number of natural products containing heterocyclic moieties as MAPK signalling pathway inhibitors have been put together. The structure activity relationship along with docking studies have been discussed to apprehend the mechanistic studies of various compounds that will ultimately help to design and develop more MAPK signalling pathway inhibitors. [ABSTRACT FROM AUTHOR]

Heterocyclic compounds hold a pivotal place in medicinal chemistry due to their wide range of biological activities and thus, are exhaustively explored in the field of drug design and development. Continuous efforts are being carried out for the development of medicinal agents especially, for dreadful diseases like cancer. Thiophene, a sulfur containing heterocyclic scaffold, has emerged as one of the relatively well-explored scaffold for the development of library of molecules having potential anticancer profile. Thiophene analogs have been reported to bind with a wide range of cancer-specific protein targets, depending on the nature and position of substitutions. Accordingly, thiophene analogs have been reported to cause their biological action through inhibition of different signaling pathways involved in cancer. Functionally, different anticancer targets require different structural features, so researchers have tried to synthesize new thiophene derivatives with varied substitutions. In the present review, authors have presented the information available on thiophene-based molecules as anticancer agents with special focus on synthetic methodologies, biological profile and structure activity relationship (SAR) studies. Various patents granted for thiophene containing molecules as anticancer have also been included. [ABSTRACT FROM AUTHOR]

• TZDs, an important pharmacophore in the treatment of diabetes. • Various analog-based synthetic strategies and biological significance are discussed. • Clinical studies using TZDs along with other antidiabetic agents are also highlighted. • SAR has been discussed to suggest the interactions between derivatives and receptor sites. • Pyrazole, chromone, and acid-based TZDs can be considered as potential lead molecules. Diabetes or diabetes mellitus is a complex or polygenic disorder, which is characterized by increased levels of glucose (hyperglycemia) and deficiency in insulin secretion or resistance to insulin over an elongated period in the liver and peripheral tissues. Thiazolidine-2,4-dione (TZD) is a privileged scaffold and an outstanding heterocyclic moiety in the field of drug discovery, which provides various opportunities in exploring this moiety as an antidiabetic agent. In the past few years, various novel synthetic approaches had been undertaken to synthesize different derivatives to explore them as more potent antidiabetic agents with devoid of side effects (i.e., edema, weight gain, and bladder cancer) of clinically used TZD (pioglitazone and rosiglitazone). In this review, an effort has been made to summarize the up to date research work of various synthetic strategies for TZD derivatives as well as their biological significance and clinical studies of TZDs in combination with other category as antidiabetic agents. This review also highlights the structure-activity relationships and the molecular docking studies to convey the interaction of various synthesized novel derivatives with its receptor site. [ABSTRACT FROM AUTHOR]

• The manuscript describes the simple synthetic protocol towards potent multiple-action 2,4-thiazolidinedione derivatives. • The corroboration of the pharmacological activity with in-silico evaluation has also been reported. • The compounds are promising dual action or even triple action drug candidates. • Free radicals responsible for inflammation can be curbed thus tackling inflammation. A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, 1H NMR, 13C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential. [ABSTRACT FROM AUTHOR]

Cancer is the world's major health issue, scavenging lives of millions throughout the world. A number of anticancer drugs have figured prominently in the diagnosis and treatment of various malignancies. However, despite significant advances, medications produced have fallen short of expectations, and cancer research is now at a crossroads, necessitating a paradigm shift in designing of new anticancer agents with multitargeted effect which not only increases drug efficacy but also nullifies associated drug side-effects. Purine moiety encompasses essential biomolecules like DNA, RNA, ATP, the nicotinamide adenine dinucleotide (NAD) coenzyme, alkaloids etc. Therefore, its synthetic derivatives and investigation are of tremendous interest in the development of associated effective medications. Purine possessing heterocyclic compounds can be honoured with considerable anticancer activities, and tampered with variety of sites wherein, numerous purine derivatives have already got approval to treat cancer. This article describes various hybrids of purine with other heterocyclic moieties as a novel anticancer medicine synthesized in the last decade in consideration for the challenge of drug resistance in cancer therapy. In the hunt for more successful and less hazardous treatment approaches, this paper illustrates numerous derivatives and hybrids of purine as anticancer medications along with possible structure-activity relationship studies, mechanistic studies, docking studies, and in silico findings. This article will be highly useful for the scientific community and offer perspectives that how these scaffolds as privileged structures might be exploited in the future for rational design and discovery of purine based anticancer agents. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Sodium channel inhibitors are the promising target for the management of convulsions. • Detailed pharmacology of sodium channel. • Development of anticonvulsant drugs as voltage gated sodium channel inhibitors. • Detailed pharmacological activity, SAR and possible mechanisms is discussed. Voltage-gated sodium channel blockers are one of the vital targets for the management of several central nervous system diseases, including epilepsy, chronic pain, psychiatric disorders, and spasticity. The voltage-gated sodium channels play a key role in controlling cellular excitability. This reduction in excitotoxicity is also applied to improve the symptoms of epileptic conditions. The effectiveness of antiepileptic drugs as sodium channel depends upon the reversible blocking of the spontaneous discharge without blocking its propagation. There are number of antiepileptic drug(s) which are in pipeline to flour the market to conquer abnormal neuronal excitability. They inhibit the seizures through the inhibition of complex voltage- and frequency-dependent ionic currents through sodium channels. Over the past decade, the sodium channel is one of the most explored targets to control or treat the seizure, but there has not been any game-changing discovery yet. Although there are large numbers of drugs approved for the treatment of epilepsy, however they are associated with several acute to chronic side effects. Many research groups have tirelessly worked for better therapeutic medication on this popular target to treat epileptic seizures. The review quotes briefly the developments of the approved examples of sodium channel blockers as anticonvulsant drugs. Medicinal chemists have tried the design and development of some more potent anticonvulsant drugs to minimize the toxicity that are discussed here, and an emphasis is given for their possible mechanism and the structure–activity relationship (SAR). [ABSTRACT FROM AUTHOR]

• Synthesis of Thiazolidinedione-pyrazole conjugates. • In vivo antidiabetic activity. • In vitro anti inflammatory activity. • In vitro anti oxidant activity. • Structure activity relationship established. • Molecular docking against PPAR-γ and alpha-amylase. A series of fourteen novel thiazolidine-2,4-dione derivatives clubbed with pyrazole moiety were synthesized via four step reaction procedure. Reactions were monitored by thin layer chromatography and were characterized by physicochemical and spectrophotometric (IR, Mass, 1HNMR and 13CNMR) analysis. The spectral data were in good agreement with their structures. The title compounds were docked against peroxisome proliferated activated receptors (PPAR-γ) and alpha-amylase and further evaluated for in vivo and in vitro antidiabetic, in vitro anti-inflammatory and antioxidant activities. Compound GB14 exhibited significant blood glucose lowering activity and was also found to be active inhibitor of alpha-amylase. Compound GB7 was found to be potent anti-inflammatory agent in terms of reducing inflammatory markers (TNF-α, IL-β, MDA) and also showed antioxidant activity to good extent. Therefore, these compounds may be considered as promising candidates for the development of new antidiabetic agents. [ABSTRACT FROM AUTHOR]