Role of heterocycles in inhibition of VEGFR-2 - a recent update (2019-2022).

The literature reveals that oncogenic protein kinase inhibition has been proved to be a successful anticancer approach. The vascular endothelial growth factor receptor (VEGFR) kinase plays an important role in angiogenesis and metastasis. VEGFR-2 has an upper hand in the angiogenesis process. Vascular endothelial growth factor activates VEGFR-2 which initiates tumor angiogenesis. In addition, VEGFRs are associated with numerous other diseases. Hence, inhibition of VEGFRs is an attractive approach for cancer treatment. In view of this, researchers designed and discovered small molecular heterocycle-based VEGFR-2 inhibitors and some of them have been approved by the Food and Drug Administration (FDA). However, these VEGFR-2 inhibitors pose adverse side effects such as cardiovascular problems, diarrhea, and renal function impairment. Research indicates that combination of certain pharmacophores exhibits excellent VEGFR inhibitory activity. In particular, combination of heterocycles paved the way to efficient VEGFR inhibitors. In this review, the research focusing on VEGFR inhibitory activity has been discussed along with the structure-activity relationship. In addition to emphasizing the most potent molecule among the set of designed molecules, structural features responsible for such an activity are described. This review may aid in designing potent VEGFR inhibitors.

Recent Advances (2015-2020) in Drug Discovery for Attenuation of Pulmonary Fibrosis and COPD.

A condition of scarring of lung tissue due to a wide range of causes (such as environmental pollution, cigarette smoking (CS), lung diseases, some medications, etc.) has been reported as pulmonary fibrosis (PF). This has become a serious problem all over the world due to the lack of efficient drugs for treatment or cure. To date, no drug has been designed that could inhibit fibrosis. However, few medications have been reported to reduce the rate of fibrosis. Meanwhile, ongoing research indicates pulmonary fibrosis can be treated in its initial stages when symptoms are mild. Here, an attempt is made to summarize the recent studies on the effects of various chemical drugs that attenuate PF and increase patients' quality of life. The review is classified based on the nature of the drug molecules, e.g., natural/biomolecule-based, synthetic-molecule-based PF inhibitors, etc. Here, the mechanisms through which the drug molecules attenuate PF are discussed. It is shown that inhibitory molecules can significantly decrease the TGF-ß1, profibrotic factors, proteins responsible for inflammation, pro-fibrogenic cytokines, etc., thereby ameliorating the progress of PF. This review may be useful in designing better drugs that could reduce the fibrosis process drastically or even cure the disease to some extent.

Pyrazolopyrimidines as attractive pharmacophores in efficient drug design: A recent update.

Among the menacing diseases, cancer needs the most attention as millions of people are affected by it worldwide. Genetic and environmental factors play a pivotal role in causing cancer. Although a wide range of underlying mechanisms of cancer has been discovered, efficient treatments have not been discovered to date. Additionally, diseases caused by microbes such as viruses, bacteria, protozoa, and so forth, persistently result in several deaths. Also, inflammation is a major factor that leads to several health issues. For decades, drug design has become a major part of drug discovery and development for curing various diseases. Among the large number of pharmacological agents that have been synthesized, only very few have emerged as efficient drug molecules. Most of them are heterocyclic compounds, which are promising candidates for the design of efficient drug molecules. Furthermore, fused heterocycles showed comparatively stronger pharmacological activities than monocyclic heterocycles. The literature reveals that pyrazolopyrimidines have outstanding biological activity. Hence, here, the diverse pharmacological activities shown by pyrazolopyrimidine derivatives reported in the last 5 years are collated and reviewed systematically. This review is classified into various sections focusing on anticancer, antimicrobial, anti-inflammatory, and enzyme inhibitors. Structure-activity relationships are discussed in brief, which will help researchers design potent pharmacological agents.

Promising heterocycle-based scaffolds in recent (2019-2021) anti-Alzheimer's drug design and discovery.

Alzheimer's disease (AD) is one of the neurodegenerative diseases that led to morbidity and mortality world-wide. It is a complex disease whose etiology is not completely known that leads to difficulty in prevention or cure of the AD. Also, there are only few approved drugs for AD treatment. Apart from deaths due to AD, expenditure of treatment and care of AD patients is higher than that of treatment of HIV and cancer diseases combined. Hence, it leads to an economic burden also. Although research is being carried out on designing drugs for AD, most of them have ended up in poor inhibitors with high toxicity. Hence, researchers should shoulder a great responsibility of discovery of efficient drugs for AD treatment. In the field of drug discovery, heterocycles played an important role. Also, most of the heterocyclic scaffolds have been used in design of potent anti-AD agents. In view of this, heterocyclic molecules reported recently are compiled and evaluated comprehensively. Especially, the molecules which exhibited pronounced activity are emphasized and described with respect to structure-activity relationship (SAR) in brief.

Pharmacological report of recently designed multifunctional coumarin and coumarin-heterocycle derivatives.

Coumarin is a naturally available molecule and has been identified as a potent pharmacophore due to its pharmacological activity. Because of this, coumarin has been exploited synthetically to prepare a wide range of derivatives. In fact, most coumarin derivatives have been found to be less toxic, which is the most essential property for a drug molecule. Such molecules are being prepared for therapeutic use as broad-spectrum pharmacological agents. Microbial diseases including viral diseases have become very common and are responsible for many deaths worldwide. In particular, microbial drug resistance is a problem that needs to be tackled in an effective manner. Also, for Alzheimer's disease, which affects most elderly persons, no efficient chemotherapy exists. In addition, although diabetes, a metabolic syndrome, can be treated with many drugs, there is no complete cure. Thus, more potent antidiabetic agents are required for the management of diabetes. Likewise, for the treatment of a wide range of ailments caused by microbes, genetic factors, or lifestyle-related factors, an efficient drug regimen is needed. In view of this, coumarin derivatives are designed and evaluated. Here, coumarin derivatives that have been reported recently are compiled, classified and evaluated critically. This study briefly takes the structure-activity relationship into consideration and suggests the next suitable step. With a focus on the most potent molecules, the pharmacological activity of the evaluated molecules is described.

Recent update on antibacterial and antifungal activity of quinoline scaffolds.

Although most of the heterocycles have been reported to possess a significant pharmacological activity, only a few of them, namely quinoline derivatives, have exhibited the finest biological activities. Despite the few medicinal properties of the plain quinoline molecule, its derivatives exhibit diverse pharmacological properties such as anticancer, anti-inflammatory, antibacterial, antiviral, antifungal, antiprotozoal activities, and so on. The potential antimicrobial properties of the quinoline derivatives are evident from the decades of research on these derivatives. Owing to limitations like drug resistance, high cost, severe side effects, and less bioavailability of previously synthesized antimicrobial agents, these drugs have become obsolete in recent years. Hence, the design of more efficient antimicrobial drugs must be given topmost priority. A breakthrough in drug discovery is a must to prevent malevolent microbial diseases. Addressing all these issues, researchers have been continuously contributing to antimicrobial drug discovery. Herein, a short description of the pharmacology of antimicrobial agents such as antibacterials and antifungals synthesized recently is provided. The versatile derivatization of the quinoline moiety leading to significant antimicrobial potencies is discussed, considering the structure-activity relationship.

Synthesis, pharmacological evaluation and structure-activity relationship of recently discovered enzyme antagonist azoles.

Global people are suffering from the legion of diseases. Cytotoxic property of the chemical compound would not solely influence effective drug properties and reduce unnecessary side effects. Proteins/enzymes responsible for microbe proliferation or survival are specifically targeted and inhibited successfully making the cells to undergo apoptosis. Furthermore, isoforms of essential enzymes have distinct physiological functions; thereby inhibition of essential enzyme isoforms is an apt way to the clinical approach of disease neutralization. Drugs are designed so as to play significant roles such as signaling pathways in the oncogenic process including cell proliferation, invasion, and angiogenesis. The present review comprises collective information of the recent synthesis of various organic drug compounds in brief, which could inhibit particular enzyme. The review also covers the correlation of the structure of a drug molecule designed and its inhibitory activity. Also, the most significant enzyme inhibitors are highlighted and structural moieties/core units responsible for remarkable inhibitory values are emphasized.

Indole - a promising pharmacophore in recent antiviral drug discovery.

The bicyclic molecule indole has been in the limelight because of its numerous pharmacological potencies. It is used as an excellent scaffold in drug discovery of medicinal drugs such as antimicrobials, anticancer agents, antihypertensives, anti-proliferative agents and anti-inflammatory agents. In spite of its diverse therapeutic activity, it is used as a key pharmacophore in synthesizing the most potent biological agents. Besides, viral infections are ubiquitous and their prevention and cure have become a great challenge. In this regard, the design of indole-containing antiviral drugs is accomplished to combat viral infections. A lot of research is being carried out towards antiviral drug discovery by many researchers round the clock. Herein, the antiviral activity of recently discovered indole scaffolds is compiled and critically evaluated to give a meaningful summary. In addition, the structure-activity relationship of remarkable antiviral agents is discussed. Also, the structural motifs attributed to noteworthy antiviral properties are highlighted to guide future antiviral research.

Critical evaluation of current Alzheimer's drug discovery (2018-19) & futuristic Alzheimer drug model approach.

Alzheimer's disease (AD), a neurodegenerative disease responsible for death of millions of people worldwide is a progressive clinical disorder which causes neurons to degenerate and ultimately die. It is one of the common causes of dementia wherein a person's incapability to independently think, behave and decline in social skills can be quoted as major symptoms. However the early signs include the simple non-clinical symptoms such as forgetting recent events and conversations. Onset of these symptoms leads to worsened conditions wherein the AD patient suffers severe memory impairment and eventually becomes unable to work out everyday tasks. Even though there is no complete cure for AD, rigorous research has been going on to reduce the progress of AD. Currently, a very few clinical drugs are prevailing for AD treatment. So this is the need of hour to design, develop and discovery of novel anti-AD drugs. The main factors for the cause of AD according to scientific research reveals structural changes in brain proteins such as beta amyloid, tau proteins into plaques and tangles respectively. The abnormal proteins distort the neurons. Despite the high potencies of the synthesized molecules; they could not get on the clinical tests up to human usage. In this review article, the recent research carried out with respect to inhibition of AChE, BuChE, NO, BACE1, MAOs, Aß, H3R, DAPK, CSF1R, 5-HT4R, PDE, σ1R and GSK-3ß is compiled and organized. The summary is focused mainly on cholinesterases, Aß, BACE1 and MAOs classes of potential inhibitors. The review also covers structure activity relationship of most potent compounds of each class of inhibitors alongside redesign and remodeling of the most significant inhibitors in order to expect cutting edge inhibitory properties towards AD. Alongside the molecular docking studies of the some final compounds are discussed.

Synthesis of sydnone substituted Biginelli derivatives as hyaluronidase inhibitors.

A novel series of Biginelli 2-3 (a and b) and Biginelli-like compounds 4-7 (a and b) were synthesized from 3-aryl-4-formylsydnone 1 (a and b). Since the crystal structure of hyaluronidase was unavailable, the human hyaluronidase protein structure was used as template and homology modeling was performed, validated by Ramachandran plots and subjected to docking studies along with in vitro anti-inflammatory activity assessment against hyaluronidase. Compounds 2-3 (a and b) exhibited potent enzyme inhibition.

Synthesis, characterization and in vitro anticancer evaluation of novel 1,2,4-triazolin-3-one derivatives.

A series of novel 2-(4-chlorophenyl)-5-methyl-4-(2-amine/oxy-ethyl)-2,4-dihydro-[1,2,4]triazol-3-one (5a-t) were synthesized and in vitro anticancerous action of the resulting compounds was studied against NCI-60 Human Tumor Cell Line at a single high dose (10(-5) M) concentration for primary cytotoxicity assay. Among the tested compounds (5a-e, 5g-h, 5k, 5p), the compound 5g (NSC: 761736/1) was further evaluated for five dose criteria at five different minimal concentrations against the full panel of 60 human tumor cell lines which exhibited activity against Leukemia (GI50: 1.10 µM), Non-Small Cell Lung Cancer (GI50: 1.00 µM), Renal Cancer (GI50: 1.00 µM), Colon Cancer (GI50: 1.66 µM), CNS Cancer (GI50: 1.36 µM), Melanoma (GI50: 1.82 µM), Ovarian Cancer (GI50: 1.64 µM) and Breast Cancer (GI50: 1.69 µM).