Covalent inhibitors: An ambitious approach for the discovery of newer oncotherapeutics.

Covalent inhibitors have been used to treat several diseases for over a century. However, strategic approaches for the rational design of covalent drugs have taken a definitive shape in recent times. Since the first appearance of covalent inhibitors in the late 18th century, the field has grown tremendously and around 30% of marketed drugs are covalent inhibitors especially, for oncology indications. However, the off-target toxicity and safety concerns can be significant issues related to the covalent drugs. Covalent kinase inhibitor (CKI) targeted oncotherapeutics has advanced dramatically over the last two decades since the discovery of afatinib (Gilotrif®), an EGFR inhibitor. Since then, US FDA has approved 10 CKIs for diverse cancer targets. The present review broadly summarizes the ongoing development in the discovery of newer CKIs from 2016 till the end of 2022. We believe that these efforts will assist the modern medicinal chemist actively working in the field of CKI discovery for varied indications.

Hit discovery of novel 2-phenyl-substituted 4-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidines as potential anti-glioblastoma therapeutics: Design, synthesis, biological evaluation, and computational screening.

Glioblastoma multiforme (GBM) is a highly-aggressive, dreadful disease with poor prognosis and disappointing clinical success. There is an unmet medical need of molecularly-targeted therapeutics for GBM treatment. In the present work, a series of novel 2-phenyl-substituted 4-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidines was designed, synthesized, purified, characterized, and evaluated for cytotoxicity against glioblastoma cell line U87-MG. The design process (virtual library enumeration around the core, physicochemical and molecular property prediction/calculation of the designs, filtering the undesirable ones, and the diversity analyses of the lead-like designs), was carefully curated so as to obtain a set of structurally-diverse, novel molecules (total 20), with a particular focus on the relatively unexplored core structure, 6,7-dihydro-5H-cyclopenta[d]pyrimidine. The preliminary screening was done using MTT assay at 10 and 100 µM concentrations of the title compounds F1 -F20 and positive control cisplatin, which yielded six hits (% inhibition at 10 µM: ~50%)-F2 , F3 , F5 , F7 , F15 , and F20 , which were taken up for IC50 determination. The top hits F2 and F7 (IC50 < 10 µM) were further used for computational studies such as target prediction, followed by their molecular docking in the binding sites of the top-3 predicted targets (epidermal growth factor receptor kinase domain, cyclin-dependent kinase 2 [CDK2]) /cyclin E, and anaplastic lymphoma kinase [ALK]). The docking pose analyses revealed interesting trends. The relatively planar core structure, presence of favorable hinge-binding substructures, basic groups, all added up, and culminated in appreciable cytotoxicity against GBM cell line.

Protein Informatics and Vaccine Development: Cancer Case Study.

Clinical translation is a challenging step in the development of cancer vaccines and is found to be related to the complex nature of cancer immunology. Vaccine-based therapeutic strategies for cancer have gained consideration with the advent of vaccine technology as well as an understanding of cancer immunology. Immunotherapy has been widely used in the treatment of cancer. Some promising candidates have been identified to engineer cancer vaccines like Glycoprotein, Mucin 1, MHC protein, etc. It has benefited from the availability of advanced techniques for rapid identification and selection of proteins for precision engineering. Simultaneously, nanovaccines have been focused on target delivery and artificial intelligence-based approaches for personalized vaccine development. The manuscript summarizes the advances in the development of structurebased cancer vaccines along with the status of clinical studies and applications.

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis.

Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole (IIIa-m) and aziridine (VIa and VIc) were afforded through a modified Schiff base green synthesis using ß-cyclodextrin-SO3H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with ß-cyclodextrin-SO3H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids (IIIa-m) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones (IVa-m) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C-S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC50 = 1.47 µM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC50 = 1.40 µM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc, and the results suggested that these two compounds could be potential leads for the treatment of cancer.

Molecular Insights into Coumarin Analogues as Antimicrobial Agents: Recent Developments in Drug Discovery.

A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure-activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics.

Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery.

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016-2020. The structure-activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.

A Concise Analytical Profile of Efavirenz: Analytical Methodologies.

Non-nucleoside reverse transcriptase inhibitors are the prime members of antiretroviral therapy that are presently employed for the management of the human immunodeficiency virus. It uses an enzyme i.e., reverse transcriptase to convert its ribonucleic acid into reverse transcription; these agents impede the function of reverse transcriptase and reverse transcription counter human immunodeficiency virus from replicating. Efavirenz is the first-generation non-nucleoside reverse transcriptase inhibitor agent. Similar to the other non-nucleoside reverse transcriptase inhibitor agents; it is prescribed with other inhibitors in combination for regimens antiretroviral therapy. To enhance survival and avoid aggressive infections in patients affected with human immunodeficiency virus infection, adequate antiretroviral therapy is the most significant treatment. Accordingly, the development and validation of such therapeutic agents are challenging work for the analysts. Therefore, the proposed review integrally addresses the analytical reports of efavirenz recorded in the literature databases like Scopus, Web of Science, Google Scholar, Pub-Med, and through many other sources. It has been remarked that for the development of efavirenz many analytical techniques were used for addressing the qualitative and quantitative estimation of efavirenz from various pharmaceutical and biological matrices. This review plan to review the stereochemistry, mechanism of action, resistance, pharmacokinetics, pharmacodynamics, safety and adverse reaction, and various analytical approaches assessed for the same. The hyphenated and chromatographic techniques are frequently used for analysis of cited drug.

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences.

SARS-CoV-2 (2019-nCoV) emerged in 2019 and proliferated rapidly across the globe. Scientists are attempting to investigate antivirals specific to COVID-19 treatment. The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease (Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates. So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity. With the aid of in silico techniques such as molecular docking and druggability studies, we have proposed several natural active compounds including glycyrrhizin, bicylogermecrene, tryptanthrine, ß-sitosterol, indirubin, indican, indigo, hesperetin, crysophanic acid, rhein, berberine and ß-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2. Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.

ISATIN: New Hope Against Convulsion.

BACKGROUND: Epilepsy is one in every of the foremost important chronic neurological disorders with high incidence worldwide. Several epileptic patients don't seem to be fully treated with currently available marketed medicines likewise so many drugs have shown unfavorable side effect and drug interaction. Therefore, there are continuing interests to seek out new anticonvulsant drugs. METHODS: Literature search was carried out to indentify isatin containing derivatives as anticonvulsant drugs. RESULTS: Common synthetic schemes were studied to design and develop isatin derives anticonvulsant agents. Various structural features essential for the design of isatin compounds were reported. Anticonvulsant activity is evaluated by different tests were identified and their results can be considered for the design of novel isatin derivatives as anticonvulsants. CONCLUSION: In outline, isatin has been proved to be an excellent hybrid building the molecule with interesting biological activities. Among the prospect of derivatizing the N1, C2 and C3 positions, along with substitution on the aromatic ring, the synthetic modification for isatin is almost endless. Despite the fact that isatin derivatives are well-studied compounds, new derivatives are continually being discovered on the basis of known AEDs, isatin has been fused with other bioactive drug fragments and subsequently investigated as hybrid/dual action drugs and selectively targeted against convulsion.