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The ongoing research in cancer treatment underscores the significance of dual epidermal growth factor receptor (EGFR) kinase inhibitors targeting both mutant and wild-type variants. In this study, employing in silico fragment-based drug design (FBDD) and computational analysis, we have successfully developed a novel chemical series of 2-(pyrimidin-4-yl)oxazole-4-carboxamide (16a-j) derivatives designed as dual EGFR kinase inhibitors. A comparative in vitro anticancer profile of the newly synthesized compounds (16a-j) was tested against a panel of five human cancer cell lines like prostate cancer (PC3 & DU-145), lung cancer (A549), human liver cancer (HEPG2), and breast cancer (MDA-MB-468) by employing MTT method. In this experiment a well-known anticancer agent, Etoposide was used as positive control. Most of the derivatives demonstrated significant cytotoxicity, ranging from excellent to moderate levels. The IC 50 values for the synthesized compounds observed between 0.10 ± 0.052 to 9.83 ± 5.96 µM, while the positive control exhibited a range of 1.97 ± 0.45 µM to 3.08 ± 0.135 µM. These results indicate that the synthesized compounds demonstrate higher cytotoxic potency in comparison to the reference compound. Furthermore, all these compounds underwent screening against normal Vero cell lines to assess their cytotoxicity. In each case, the observed cytotoxicity values (IC 50 ) were higher than 22 µM, affirming the compounds selectivity for cancer cell lines. Among the compounds investigated, three compounds (16a, 16e, and 16i) exhibited notable cytotoxicity, while two compounds (16g and 16h) demonstrated exceptional cytotoxicity. The selectivity index of the tested compounds indicates a pronounced preference for targeting cancer cell lines over normal cells. Furthermore, all the compounds 16a-j underwent assessment for their EGFR kinase inhibitory activity against both EGFR WT and mutated EGFR T790M . The results unveiled the potential eligibility of this new series of compounds as effective EGFR inhibitors. Moreover, compound 16h underwent additional testing for cell cycle analysis, revealing its capability to arrest the cell cycle in the G2/M phase and induce apoptosis at the IC 50 concentration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nilesh Raghunath Khedkar reports financial support, administrative support, equipment, drugs, or supplies, statistical analysis, and writing assistance were provided by Lupin Ltd Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC 50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters., (© 2022 Wiley Periodicals LLC.)

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC 50 value of 6.34 μM and compound 8m displayed an IC 50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC 50  = 10.25 μM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC 50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Addressing the increasing incidences of cancer worldwide along with the multifaceted problem of drug resistance via development of new anticancer agents has become an essential goal. Due to the known cytotoxic effects and reported Akt inhibitory potential of azaindoles we designed a new framework incorporating the structural features of rosuvastatin and 5- or 7-azaindole. The framework was used to construct a library of small molecules for further pharmacological evaluation. The design was supported by the docking studies of two representative molecules in silico. A one-pot sonochemical approach was established for the synthesis of these rosuvastatin based azaindoles that involved the coupling-cyclization of a rosuvastatin derived terminal alkyne with appropriate 3-iodopyridine derivatives under Pd/Cu-catalysis. When tested using an MTT assay, some of the synthesized compounds showed desirable cytotoxic effects against three cancer cell lines e.g. HCT 116, Hep G2 and PA-1 but no significant effects against the non-cancerous HEK cell line. According to the SAR the 5-azaindole ring appeared to be marginally better than the 7-azaindole whereas the activity was varied with the variation of sulfonamide moiety attached to the N-1 atom of the azaindole ring. Among all the groups present in the sulfonamide moiety the p-MeC 6 H 4 group appeared to be most effective in terms of activity. While 3b and 5b were identified as initial hit molecules the compound 5b (in addition to 3b) also showed significant inhibition of Akt1 in vitro that was reflected by its strong interaction with Akt1 in silico (with the docking score -11.7 kcal/mol) involving two H-bonding interactions with Ser7 and Asp439 residues. Further, a reasonable ADME was predicted for 5bin silico. Being a potent inhibitor (MIA Paca-2 IC 50  = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer is one of the leading causes of death. Globally a huge number of deaths and new incidences are reported annually. Heterocyclic compounds have been proved to be very effective in the treatment of different types of cancer. Among different heterocyclic scaffolds, quinazoline and quinazolinone core were found versatile and interesting with many biological activities. In the discovery of novel anticancer agents, the Quinazoline core is very effective. The FDA has approved more than 20 drugs as an anticancer bearing quinazoline or quinazolinone core in the last two decades. One prime example is Dacomitinib, which was newly approved for non-small-cell lung carcinoma treatment in 2018. These drugs work by different pathways to prevent the spread of cancer cell progression, including inhibition of different kinases, tubulin, kinesin spindle protein, and so forth. This review presented recent developments of quinazoline/quinazolinone scaffold bearing derivatives as anticancer agents acting as epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR), and dual EGFR/VEGFR inhibitors., (© 2022 Wiley Periodicals LLC.)

As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member heteroaromatic ring with two nitrogen atoms, has a major impact in chemical industries as well as pharmaceutical industries. Due to its wide range of biological activities against various diseases, it has been identified as a biologically important heterocyclic scaffold. The treatment of neurological disorders has always been a difficult task in both the past and present. Therefore, identifying therapeutically effective molecules for neurological conditions remains an open challenge in biomedical research and development. For developing novel entities as neuroprotective agents, recently, pyrazole scaffold has attracted medicinal chemists worldwide. The major focus of research in this area is discovering novel molecules as neuroprotective agents with minimal adverse effects and better effectiveness in improving the neurological condition. This review mainly covers recent developments in the neuropharmacological role of pyrazole incorporated compounds, including their structural-activity relationship (SAR), which also further includes IC 50 values (in mM as well as in μM), recent patents, and a brief history as neuroprotective agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A new class of 3-substituted isocoumarin/3-alkylidenephthalide based novel small molecules derived from rosuvastatin were designed and synthesized via the ultrasound assisted Cu-mediated coupling-cyclization in a single pot with remarkable regioselectivity. The phthalides were generally obtained at lower temperature whereas the use of elevated temperature afforded isocoumarins. Two compounds e.g. 3n and 4d showed promising cytotoxic effects when tested against HCT 116, HepG2 and PA-1 cell lines at 10 μM. Indeed, 4d was found to be a potent cytotoxic agent (IC 50 ∼ 0.76-4.51 μM). Both 3n and 4d were tested for their effects on PANC-1 cells. Considerable decrease in p-Akt substrates shown by 4d and 3n at 50 μM (western blot analysis) indicated their ability to inhibit p-Akt signal transduction pathway and arresting growth of PANC-1 cells in vitro. This was further supported by the cytotoxic effect of 4d on PANC-1 cells (MTT assay) that was better than rosuvastatin. While none of 3n and 4d showed any significant effect on non-cancerous HEK cell line (indicating their potential selectivity towards cancer cells) these compounds were further evaluated for their toxicities in Zebrafish embryo. The NOAEL (No Observed Adverse Effect Level) for teratogenicity, hepatotoxicity and cardiotoxicity was found to be 100 μM for both compound. Thus, 4d as a novel and potent but safer cytotoxic agent with potential to treat colorectal/ovarian and pancreatic cancer is of further medicinal interest., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of novel 5-alkyl/aryl thiadiazole substituted thiazolidin-4-ones were synthesized by a two-step process. In the first step, 5-alkyl/aryl substituted 2-aminothiadiazoles were synthesized, which on reaction with substituted aromatic aldehydes and thioglycolic acid in the presence of dicyclohexylcarbodiimide afforded thiazolidin- 4-ones. All the compounds were synthesized in fairly good yields and their structures were confirmed by spectral and physical data. The title compounds were screened for in vitro anti-proliferative activity on human breast adenocarcinoma cells (MCF-7) by MTT assay. Most of the derivatives showed an IC₅₀ less than 150 μmol L⁻¹. Among the compounds tested, 2-(2-nitrophenyl)- 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3f), 2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2- -yl)-thiazolidin-4-one (3b), and 2-(4-chlorophenyl)-3- -(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3c) were found to be the most active derivatives with IC50 values of 46.34, 66.84, and 60.71 μmol L⁻¹, respectively. Antioxidant studies of all the synthesized compounds were carried out by diphenylpicrylhydrazyl (DPPH) assay. Among the compounds tested, 2-phenyl-3-(5-styryl- -1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3s) elicited superior antioxidant activity with IC₅₀ of 161.93 μmol L⁻¹.

Cisplatin is an anticancer drug extensively used against a variety of cancers. Cisplatin chemotherapy is found to manifest dose-dependent nephrotoxicity. Depletion of the renal antioxidant defence system has been suggested to be the main cause of cisplatin-induced nephrotoxicity. The purpose of this study is to investigate whether the ethanol extract of entire plant of Sphaeranthus indicus could reduce the intensity of toxicity in albino rats. Nephrotoxicity was assessed by determining the serum creatinine and urea levels and renal antioxidant status in rats after cisplatin administration (12 mg kg(-1) body weight, i.p.). The ethanol extract of S. indicus (150 and 300 mg kg(-1) body weight) was administered orally from the sixth day onwards for 10 days after cisplatin administration. The extract significantly reduced the elevated serum creatinine and urea levels. Renal antioxidant defence systems, such as superoxide dismutase, catalase, glutathione peroxidase activities and reduced glutathione level that are depleted by cisplatin therapy were restored to normal by treatment with the extract. Cisplatin-induced lipid peroxidation was also found to be markedly reduced by treatment with the extract. These results suggest that S. indicus has protective effect against cisplatin-induced nephrotoxicity, which may be attributed to its antioxidant potential.

Herein, we present a new library of 3-(2-(pyrimidin-5-yl)thiazol-4-yl)-1,2,4-oxadiazole (14a–j) as an anticancer agent designed based on in silico fragment-based drug design (FBDD). The derivatives were synthesized and characterized by 1HNMR,13CNMR, HRMS, and FT-IR. The library was named "pyrimidine-thiazole-1,2,4-oxadiazoles." In addition, the MTT assay was used to test the compounds (14a–j) for their potential anticancer activity in a panel of four human cancer cell lines, such as PC3 & DU-145 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer), and the normal Vero cell lines, using the widely used anticancer drug etoposide acting as a reference drug and positive control. The value obtained was presented as IC50 (µM). The IC50 values of the reference standard ranged from 1.97 ± 0.45 µM to 3.08 ± 0.135 µM, while the library of tested compounds showed IC50 values ranging from 0.02 ± 0.0031 µM to 10.3 ± 6.25 µM. Among the tested compounds, six of them showed promising anticancer activity: 14a, 14b, 14c, 14d, 14e and 14j. Especially, one compound, 14a, showed excellent anticancer activity in all the tested cell lines. All compounds showed selective cytotoxicity against cancer cells but not against normal Vero cells (IC50 = >19 µM), justifying the designing approach to develop a selective anticancer agent. These compounds were also subjected to docking experiments to investigate potential binding site interactions, and the results were consistent with the in vitro results. [ABSTRACT FROM AUTHOR]

Context: The study was aimed to develop a polymeric nanoparticle formulation of anticancer drug carboplatin using biodegradable polymer polycaprolactone (PCL). The formulation is intended for intranasal administration to treat glioma anticipating improved brain delivery as nasal route possess direct access to brain and nanoparticles have small size to overcome the mucosal and blood–brain barrier. Objective: Development and evaluation of carboplatin-PCL nanoparticles for brain delivery by nasal route. Methodology: Carboplatin-loaded PCL nanoparticles (CPCs) were prepared by double emulsion-solvent evaporation technique and characterized by particle size, zeta potential, entrapment efficiency, scanning electron microscopy and differential scanning calorimetry. The CPCs were assessed forin vitrorelease kinetics,ex vivopermeation andin situnasal perfusion. Cytotoxic potential of CPCsin vitrowas evaluated on LN229 human glioblastoma cells. Results and discussion: The optimized formulation of carboplatin-PCL nanoparticle CPC-08 with particle size of 311.6 ± 4.7 nm and zeta potential −16.3 ± 3.7 mV exhibited percentage entrapment efficiency of 27.95 ± 4.21.In vitrodrug release showed initial burst release followed by slow and continues release indicating biphasic pattern. Theex vivopermeation pattern through sheep nasal mucosa also exhibited a similar release pattern as forin vitrorelease studies.In situnasal perfusion studies in Wistar rats demonstrate that CPCs show better nasal absorption than carboplatin solution.In vitrocytotoxicity studies on LN229 cells showed an enhancement in cytotoxicity by CPCs compared to carboplatin alone. Conclusion: CPC-08 effectively improves nasal absorption of carboplatin and can be used for intranasal administration of carboplatin for improved brain delivery. [ABSTRACT FROM AUTHOR]

• Rosuvastatin based novel 3-methyleneisoindolin-1-ones were explored as Akt1 inhibitors. • The Cu-catalyzed coupling-cyclization was used for their sonochemical synthesis. • 3b showed selective cytotoxic effects on cancer cells over non-cancerous cell. • 3b reduced p-Akt substrates / cell viability on PANC-1 cell and inhibited Akt1. • With no lipid lowering / good safety in Zebrafish 3b is a potential anticancer agent. The Sonochemical synthesis of a library of 3-methyleneisoindolin-1-one based novel small molecules derived from rosuvastatin designed as potential anticancer agents was undertaken. A Cu-mediated coupling-cyclization strategy was employed to prepare this new class of compounds in a single pot with notable regioselectivity. The use of a terminal alkyne containing the propargylic ether moiety seemed to be responsible for the observed regioselectivity. Evaluation of all these compounds against three cancer cell lines e.g. HCT 116, HepG2 and PA-1 and a non-cancerous HEK cell line resulted in the identification of compound 3b as a promising cytotoxic agent with IC 50 of 3.34 ± 0.38 and 1.16 ± 0.20 µM against HCT 116 and PA-1, respectively. In another study 3b showed significant decrease in p-Akt substrates (western blot analysis) indicating its ability to inhibit the p-Akt signal transduction pathway and arresting the growth of PANC-1 cells in vitro. Indeed, 3b showed better cytotoxic effect on PANC-1 cells over rosuvastatin (MTT assay). Notably, the lack of any significant effect of 3b on non-cancerous HEK cell line suggested its potential selectivity towards cancer cells. Further, a reasonable ADME (in silico) was predicted for 3b that showed acceptable stability against rat liver microsomes in vitro. The compound also showed acceptable NOAEL (No Observed Adverse Effect Level ~ 100 µM) for teratogenicity and cardiotoxicity when evaluated for toxicities in Zebrafish embryo. Finally, unlike rosuvastatin the compound 3b did not show any lipid lowering effects in Zebrafish larvae. Overall, as a novel and promising but safer cytotoxic agent 3b could be useful for the potential treatment of colorectal / ovarian and pancreatic cancer. [Display omitted] [ABSTRACT FROM AUTHOR]