Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

A new ship tracing technology from oil spills based on multi-source data.

Oil spill from ship can cause serious pollution to the Marine environment, but it is very difficult to find and confirm the troublemaker. In order to determine the oil spill ship, this paper proposes a new method to trace the source of ship oil spills and find the suspected ship that spills oil based on SAR imagery, AIS data and related marine environment data. First, we filter AIS data based on position of oil spill areas on remote sensing imagery and convert oil spill areas into trajectory points. Secondly, based on the Lagrangian particle motion model, a bidirectional drift model is proposed to calculate the average similarity between the forward and backward drift results. Finally, the most likely oil spill ship is determined according to the average similarity results. The results of the case study show that the method is effective and practical.

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential.

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix "pril," have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N-nitroso ramipril and N-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N-nitroso ramipril and N-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar "pril" NDSRIs.

A Promising Paradigm Shift in Cancer Treatment with FGFR Inhibitors.

FGFR have been demonstrated to perform a crucial role in biological processes but their overexpression has been perceived as the operator component in the occurrence and progression of different types of carcinoma. Out of all the interest around cancer, FGFR inhibitors have assembled pace over the past few years. Therefore, FGFR inhibitors are one of the main fundamental tools to reverse drug resistance, tumor growth, and angiogenesis. Currently, many FGFR inhibitors are under the development stage or have been developed. Due to great demand and hotspots, different pharmacophores were approached to access structurally diverse FGFR inhibitors. Here, we have selected to present several representative examples such as Naphthyl, Pyrimidine, Pyridazine, Indole, and Quinoline derivatives that illustrate the diversity and advances of FGFR inhibitors in medicinal chemistry. This review focuses on the SAR study of FGFR inhibitors last five years which will be a great future scope that influences the medicinal chemist to work towards more achievements in this area.

Peptidomimetic inhibitors of the VEGF-A165/NRP-1 complex obtained by modification of the C-terminal arginine.

Inhibitors of the interaction between Neuropilin-1 (NRP-1) and Vascular Endothelial Growth Factor-A165 (VEGF-A165) hold significant promise as therapeutic and diagnostic agents directed against cancers overexpressing NRP-1. In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)1-Xaa2-Xaa3-Arg4 have been previously discovered. In the current work, we focused on Lys(Har)-Dap/Dab-Pro-Arg sequence. The aim was to examine whether replacing C-terminal Arg with its homologs and mimetics would yield more stable yet still potent inhibitors. Upon considering the results of modelling and other factors, ten novel analogues with Xaa4 = homoarginine (Har), 2-amino-4-guanidino-butyric acid (Agb), 2-amino-3-guanidino-propionic acid (Agp), citrulline (Cit), 4-aminomethyl-phenylalanine [Phe(4-CH2-NH2)] were designed, synthesized and evaluated. Two of the proposed modifications resulted in inhibitors with activity slightly lower [e.g. IC50 = 14.3 µM for Lys(Har)-Dab-Pro-Har and IC50 = 19.8 µM for Lys(Har)-Dab-Pro-Phe(4-CH2-NH2)] than the parent compounds [e.g. IC50 = 4.7 µM for Lys(Har)-Dab-Pro-Arg]. What was a surprise to us, the proteolytic stability depended more on position two of the sequence than on position four. The Dab2-analogues exhibited half-life times beyond 60 h. Our results build up the knowledge on the structural requirements that effective VEGF-A165/NRP-1 inhibitors should fulfil.

Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights.

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

Ten years of oil pollution detection in the Eastern Mediterranean shipping lanes opposite the Egyptian coast using remote sensing techniques.

The Eastern Mediterranean region, a vital conduit for global maritime trade, faces significant environmental challenges due to marine pollution, particularly from oil spills. This is the first study covering the long period of comprehensive monitoring of oil pollution using the full mission of Sentinel-1 Synthetic Aperture Radar (SAR) data in the Mediterranean Sea, so this research aims to detect and analyze comprehensively the occurrence of oil spills in the Eastern Mediterranean over a decade (2014-2023). This study focuses on identifying geographical distribution patterns, proximity to shorelines, frequency across maritime zones, and potential sources of these spills, especially around major ports and maritime routes. This study utilizes SAR data from the Sentinel-1 satellite. The methodology included automated detection algorithms within the Sentinel application platform (SNAP) and integration with GIS mapping to study oil spill patterns and characteristics. Over 1000 Sentinel-1 scenes were investigated in the northern Mediterranean waters off the coast of Egypt, to detect and analyze 355 oil spill events with a total impacted area of more than 6000 km2. The analysis of temporal spill distribution reveals significant fluctuations from year to year. Within the entire timeline of the study, 2017 had the largest spatial areas covering one thousand square kilometers. In contrast, the single largest spill recorded during the study period occurred in 2020, covering 198.73 square kilometers. The results identified a non-uniform distribution of oil spills and primarily exhibiting elongated patterns aligned with the navigation routes. The distinct increase of oil spill incidents was within the Exclusive Economic Zone (EEZ), obviously drifted to the coastline and around major ports. The study emphasizes the critical role of remote sensing technologies in addressing environmental challenges caused by the maritime transport sector, advocating for enhanced monitoring and regulatory enforcement to protect marine ecosystems and support sustainable naval activities. The findings highlight the urgent need for targeted continuous monitoring and rapid response strategies in high-traffic maritime areas, particularly around the EEZ and major ports.

Advancements in targeting tumor suppressor genes (p53 and BRCA 1/2) in breast cancer therapy.

Globally, among numerous cancer subtypes, breast cancer (BC) is one of the most prevalent forms of cancer affecting the female population. A female's family history significantly increases her risk of developing breast cancer. BC is caused by aberrant breast cells that proliferate and develop into tumors. It is estimated that 5-10% of breast carcinomas are inherited and involve genetic mutations that ensure the survival and prognosis of breast cancer cells. The most common genetic variations are responsible for hereditary breast cancer but are not limited to p53, BRCA1, and BRCA2. BRCA1 and BRCA2 are involved in genomic recombination, cell cycle monitoring, programmed cell death, and transcriptional regulation. When BRCA1 and 2 genetic variations are present in breast carcinoma, p53 irregularities become more prevalent. Both BRCA1/2 and p53 genes are involved in cell cycle monitoring. The present article discusses the current status of breast cancer research, spotlighting the tumor suppressor genes (BRCA1/2 and p53) along with structural activity relationship studies, FDA-approved drugs, and several therapy modalities for treating BC. Breast cancer drugs, accessible today in the market, have different side effects including anemia, pneumonitis, nausea, lethargy, and vomiting. Thus, the development of novel p53 and BRCA1/2 inhibitors with minimal possible side effects is crucial. We have covered compounds that have been examined subsequently (2020 onwards) in this overview which may be utilized as lead compounds. Further, we have covered mechanistic pathways to showcase the critical druggable targets and clinical and post-clinical drugs targeting them for their utility in BC.

Therapeutic potential of anticancer activity of nitrogen-containing heterocyclic scaffolds as Janus kinase (JAK) inhibitor: Biological activity, selectivity, and structure-activity relationship.

The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

Unveiling anti-diabetic potential of new thiazole-sulfonamide derivatives: Design, synthesis, in vitro bio-evaluation targeting DPP-4, α-glucosidase, and α-amylase with in-silico ADMET and docking simulation.

Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the IC50 values were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent IC50 values 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with IC50 value of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with IC50 value of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions.

Targeting cancer using scaffold-hopping approaches: illuminating SAR to improve drug design.

Scaffold hopping is a design approach involving alterations to the core structure of an already bioactive scaffold to generate novel molecules to discover bioactive hit compounds with innovative core structures. Scaffold hopping enhances selectivity and potency while maintaining physicochemical, pharmacodynamic (PD), and pharmacokinetic (PK) properties, including toxicity parameters. Numerous molecules have been designed based on a scaffold-hopping strategy that showed potent inhibition activity against multiple targets for the diverse types of malignancy. In this review, we critically discuss recent applications of scaffold hopping along with essential components of medicinal chemistry, such as structure-activity relationship (SAR) profiles. Moreover, we shed light on the limitations and challenges associated with scaffold hopping-based anticancer drug discovery.

Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line.

In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-ß-homotryptophan conjugates of 3-ß-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.

Inhibitors and PROTACs of CDK2: challenges and opportunities.

INTRODUCTION: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors. AREA COVERED: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments. EXPERT OPINION: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Oleanolic Acid Dimers with Potential Application in Medicine-Design, Synthesis, Physico-Chemical Characteristics, Cytotoxic and Antioxidant Activity.

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds' Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC50 value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

Promising anti-proliferative indolic benzenesulfonamides alter mechanisms with sulfonamide nitrogen substituents.

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7-109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.

Exploring the Darobactin Class of Antibiotics: A Comprehensive Review from Discovery to Recent Advancements.

The prevalence of antimicrobial resistance in Gram-negative bacteria poses a greater challenge due to their intrinsic resistance to many antibiotics. Recently, darobactins have emerged as a novel class of antibiotics originating from previously unexplored Gram-negative bacterial species such as Photorhabdus, Vibrio, Pseudoalteromonas and Yersinia. Darobactins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) class of antibiotics, exhibiting selective activity against Gram-negative bacteria. They target the ß-barrel assembly machinery (BAM), which is crucial for the maturation and insertion of outer membrane proteins in Gram-negative bacteria. The dar operon in the producer's genome encodes for the synthesis of darobactins, which are characterized by a fused ring system connected via an alkyl-aryl ether linkage (C-O-C) and a C-C cross-link. The enzyme DarE, using the radical S-adenosyl-l-methionine (rSAM), facilitates the formation of these bonds. Biosynthetic manipulation of the darobactin gene cluster, along with its expression in a surrogate host, has enabled access to diverse darobactin analogues with variable antibiotic activities. Recently, two independent research groups successfully achieved the total synthesis of darobactin, employing Larock heteroannulation to construct the bicyclic structure. This paper presents a comprehensive review of darobactins, encompassing their discovery through to the most recent advancements.

Pyrazole, Pyrazoline, and Fused Pyrazole Derivatives: New Horizons in EGFR-Targeted Anticancer Agents.

Pyrazole and its derivatives remain popular heterocycles in drug design, and development. Pyrazole derivatives been extensively studied by the scientific community and as they possess a wide range of biological activity, especially anti-EGFR properies. Overexpression of EGFR signaling promotes tumor growth by inhibiting apoptosis. EGFR dysfunction has been described in several cancer. Therefore, EGFR represents a prospective target for cancer treatment. Several anti-EGFR drugs are thriving the market, notably dacomitinib, afatinib, erlotinib etc. However, almost all drugs have limited therapeutic effectiveness due to a lack of selectivity as well as substantial side effects.  To address this, innovative therapeutic anti-EGFR drugs with high effectiveness and low toxicity are needed. To combat therapeutic resistance to EGFR inhibitors, pyrazole, and pyrazole-based derivatives have been explored as a promising pharmacophore for developing novel compounds with higher potency, lower toxicity, and desirable pharmacokinetic profiles. The current review outlines the investigation of advancements towards anti- EGFR via pyrazole, pyrazoline, and fused pyrazole-based compounds and represents inclusive data on pyrazole-based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical development. We have also summarised structure-activity relationship (SAR), mechanistic studies to afford ideas for the design and development of new anti-EGFR derivatives.