Derivatives 4e Research Articles

Comprehensive study for synthesis, antiviral activity, docking and ADME study for the new fluorinated hydrazonal and indeno[1,2-b]pyridine derivatives

In this context, we synthesized a novel series of fluorinated-indeno[1,2-b]pyridin-5-one derivatives 6a-h and used spectral and elemental studies to demonstrate their structural validity. This series was achieved through the reaction of indandione with their related hydrazonal precursors 4a-h. The antiviral efficacy of sixteen derivatives, including fluorinated-indeno[1,2-b]pyridin-5-ones and their respective hydrazonal precursors, was assessed by a comprehensive screening procedure against a variety of viruses, including HSV-1, COX B3, and influenza A (H1N1). With respect to COX B3, five derivatives (4c, 4d, 4h, 6e, and 6h) had greater activity as shown by their reduced IC50 values, which ranged from 0.25 to 1268 nM. The presence of the 4‑bromo substituent in compound 4h was shown to be of significant importance in its activity against the three tested viruses; COX B3, H1N1, and HSV-1, as evidenced by the IC50 values of 0.78 µM, 5.54 µM, and 0.56 µM, respectively. Finally, ADME properties and molecular docking against Coxsackievirus B3 3C protease and RNA Polymerase of (4c, 4d, 4h, 6e, and 6h) were evaluated.

Novel cyanochalcones as potential anticancer agents: apoptosis, cell cycle arrest, DNA binding, and molecular docking studies

In the light of anticancer drug discovery and development, a new series of cyanochalcones incorporating indole moiety (5a-g) were efficiently synthesized and characterized by different spectral analysis. MTT assay was used to evaluate the antiproliferative activity of the synthesized compounds towards different cancer cells (Hela, MDA-MB-231, A375, and A549) in parallel with normal cells (HSF). Trimethoxy and diethoxy-containing derivatives (5d and 5e) displayed the most selective cytotoxic activities against cervical Hela cells with IC50 values of 8.29 and 11.82 µM, respectively, with great safety pattern toward normal HSF cells (Selectivity index: 21.3 and 13.9, respectively). Therefore, 5d and 5e were chosen to study their effects on apoptosis, cell cycle arrest, and migration of Hela cells using flow cytometric analysis and wound healing assay. They induced apoptosis and cell cycle arrest at the S phase and impaired migration of HeLa cells. Regarding their effects on the expression profile of crucial genes related to the potential anticancer activities, 5d and 5e remarkably upregulated caspase 3 and Beclin1 and downregulated cyclin A1, CDK2, CDH2, MMP9, and HIF1A using qRT-PCR and ELISA techniques. UV–Vis spectral measurement demonstrated the ability of 5d and 5e to bind CT-DNA efficiently with Kb values of 3.7 × 105 and 1 × 105 M−1, respectively. Moreover, in silico molecular docking was performed to assess the binding affinities of the compounds toward the active sites of Bcl2, CDK2, and DNA. Therefore, cyanochalcones 5d and 5e might be promising anticancer agents and could offer a scientific basis for intensive research into cancer chemotherapy. Communicated by Ramaswamy H. Sarma

Synthesis and Anti-bacterial Activity Evaluation against Mycobacterium tuberculosis of New Quinoline Derivatives Coupled with the Camphor Nucleus

Abstract: Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis (Mtb), also known as Koch’s bacillus. The involvement of latent forms and resistant strains has aggravated the situation, making the disease a serious public health problem. : The objective of the study was to synthesize and evaluate ten new compounds containing camphor nucleus coupled to quinolinic derivatives as probable inhibitors of sensitive and resistant strains of Mtb growth. : The synthesis of the final compounds, 3a-e and 4a-e, was based on the use of intermediates previously obtained, in which the coupling of the camphor nucleus to quinoline derivatives was carried out via a convergent route, which resulted in good yields (50-80%). All the final compounds were fully characterized, and the 3-dimensional molecular structure of compound 4c was determined. The antimycobacterial activities of all compounds against Mtb strains were evaluated and the cytotoxicity test was conducted using the in vitro microplate procedure with broth microdilution assay (MTT). : Compound 3e was the most active against sensitive and resistant strains, with a minimal inhibitory concentration (MIC) of 9.5 μM similar to ethambutol, a first-line drug used against the tuberculosis. The most active compound 3e was selected for the potential activity against Vero cells and it displayed no cytotoxicity at a concentration near the MIC value. : The final compounds were obtained in good yields, with derivative 3e being the most promising with high activity and low cytotoxicity. Such findings open new perspectives for drug development based on the incorporation of camphor nucleus in selected compounds.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Design, synthesis, and mechanistic insight of novel imidazolones as potential EGFR inhibitors and apoptosis inducers

As regards to the structural analysis and optimization of diverse potential EGFR inhibitors, two series of imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates were designed and constructed as potential EGFR suppressors. The cytotoxic effect of the prepared derivatives was assessed toward hepatic, breast, and prostate cancerous cells (Hep-G2, MCF-7, and PC-3). Three derivatives 3d, 3e, and 3f presented potent antiproliferative activity and selectivity against the examined tumor cells showing IC50 values at low micromolar levels. Hence, successive biological assays were applied to determine the probable mechanism of action of the new compounds. They exhibited significant EGFR suppression with an IC50 range of 0.137–0.507 µM. The most effective EGFR inhibitor 3f arrested the MCF-7 cell cycle at the S phase by inducing the apoptotic pathway that was confirmed via increasing the expression of Caspases 8, 9, and Bax, which are associated with Bcl-2 decline. Additionally, molecular docking displayed a distinctive interaction between 3f and EGFR binding pocket. Overall, this work introduces some novel imidazolyl-2-cyanoprop-2-enimidothioates and ethyl imidazolylthiomethylacrylates as potential cytotoxic and EGFR inhibitors that deserve further research in tumor therapy.

Rationale, in silico docking, ADMET profile, design, synthesis and cytotoxicity evaluations of phthalazine derivatives as VEGFR-2 inhibitors and apoptosis inducers.

New phthalazine derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors were synthesized joined to different spacers including pyrazole, α,β-unsaturated ketonic fragment, pyrimidinone and/or pyrimidinthione. A docking study was carried out to explore the suggested binding orientations of the novel derivatives inside the active site of VEGFR-2. The obtained biological data were extremely interrelated to that of the docking study. In particular, compounds 4b and 3e showed the highest activities against Michigan Cancer Foundation-7 (MCF-7) and Hepatocellular carcinoma G2 (HepG2) with half maximal inhibitory concentration (IC50) = 0.06, 0.06 μM and 0.08, 0.19 μM respectively. Our derivatives 3a-e, 4a,b and 5a,b were evaluated for their cytotoxicity against normal VERO cells. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 3.00-4.75 μM. In addition, our final derivatives 3a-e, 4a, 4b, 5a and 5b were investigated for their VEGFR-2 inhibitory activities. Derivative 4b exhibited the highest VEGFR-2 inhibitory activities at an IC50 value of 0.09 ± 0.02 μM. Derivatives 3e, 4a and 5b demonstrated good activities with IC50 values = 0.12 ± 0.02, 0.15 ± 0.03 and 0.13 ± 0.03 μM respectively. Furthermore, the activities of 4b were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution and growth inhibition. Compound 4b caused cell growth arrest in growth 2-mitosis (G2-M) phase; accumulation of cells at that phase became 6.92% after being 13.2 in control cells. Moreover, our derivatives 3e, 4b and 5b revealed a good in silico considered absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile in comparison to sorafenib.

Synthesis of novel Bis-1,2,4-Triazolo[3,4-b][1,3,4]Thiadiazines from natural camphoric acid as potential anti-candidal agents

Candida species have long been attributed to various diseases like candidiasis and systemic diseases and exacerbate the symptoms of immunocompromised patients. Candida species have enzymes that could function as drug targets to decrease their pathogenicity and eradicate the fungi. This research aimed to investigate the potency of new bis-triazolothiadiazine derivatives contained in inhibiting important enzymes of C. albicans as an example, through molecular docking simulation. Thus, a novel series of bis-triazolo[3,4-b][1,3,4]thiadiazines were designed and prepared via the reaction of the most versatile, hitherto unreported 5,5′-(1,2,2-trimethylcyclopentane-1,3-diyl)bis(4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thione) with the appropriate hydrazonoyl halides and phenacyl bromides. Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. The synthesized derivatives were tested against different species of Candida spp. The most effective compound was 6f followed by 6b, 6d, and 6e, where the inhibition zone ranged from 45 mm to 38 mm. By using molecular docking, which highlighted the important interactions with the amino acid residues Lys57, Leu77, Glu116, Gly114, Phe36, Thr58, and Glu32 at the point of binding, it was possible to determine the binding interactions of the produced derivatives to the fluconazole target fungi. The binding interaction energy was discovered to be −6.494 kcal/mol for the fungi candida albicans (PDB ID: 1IA2). The derivatives 6f and 6d, which demonstrated the highest efficacy, displayed significant conserved interactions with the amino acid residues at the binding site of the fluconazole fungi, in conjunction with the PDB co-crystal ligand 1IA2. The study’s results also revealed that the dG scores of the novel bis-triazolo-thiadiazines 6b-f. The study shows good docking scores with acceptable binding interactions. Finally, molecular docking studies revealed the lowest binding activity of derivatives 6e and 6c with the target fungi.

New pyrazole-pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, in silico studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages.

Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole-pyridazine-based hybrids, 5a-f and 6a-f, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. In vitro COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives 5f and 6f were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC50 values of 1.50 and 1.15 μM, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.

Synthesis and biological evaluation of novel D-ring fused steroidal N(2)-substituted-1,2,3-triazoles.

In this study, a series of 13 new D-ring fused steroidal N(2)-substituted-1,2,3-triazoles were synthesized, characterized and evaluated for their biological activities. The relative binding affinities of the synthesized compounds for the ligand-binding domains of estrogen receptors α and β, androgen receptor and glucocorticoid receptor demonstrated that androstane derivatives 3a and 3h and estratriene derivative 4e showed highly specific and strong binding affinity for estrogen receptor β, while 3b, 3e, 4a and 4b displayed high binding affinity for the glucocorticoid receptor. The synthesized compounds were tested for their ability to inhibit aldo-keto reductases 1C3 and 1C4 in vitro by monitoring NADPH consumption using fluorescence spectroscopy. The most potent aldo-keto reductase 1C3 inhibitors were compounds 3h (71.17%) and 3f (69.9%). Moreover, a molecular docking study was carried out for compounds 3f and 3h against aldo-keto reductase 1C3 and results showed that compounds 3h and 3f could bind in the same site and orientation as EM1404. However, polar atoms in the triazole group enable additional hydrogen bonding deeper in SP1 with Tyr319, Tyr216 and the NADP+ cofactor, which are not visible in the AKR1C3-EM1404 crystal structure. The synthesized compounds were screened for their anticancer activity against four cancer cell lines. Compound 3f demonstrated moderate toxic effects across various cancer types, while displaying lower toxicity towards the healthy cell line. In summary, our findings indicate that N(2)-substituted-1,2,3-triazoles are high-affinity ligands for estrogen receptor β and glucocorticoid receptor, inhibitors of aldo-keto reductase 1C3 enzyme, and exhibit antiproliferative effects against cancer cells, suggesting that they could serve as scaffolds for anticancer drug development.

Design, synthesis, and structure-activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors.

A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i-k (IC50 = 35-116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a-m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.

Anticancer Potential of Novel Cinnamoyl Derivatives against U87MG and SHSY-5Y Cell Lines.

Glioblastoma multiforme (GBM) is probably the most malignant and aggressive brain tumor belonging to the class of astrocytomas. The considerable aggressiveness and high malignancy of GBM make it a tumor that is difficult to treat. Here, we report the synthesis and biological evaluation of eighteen novel cinnamoyl derivatives (3a-i and 4a-i) to obtain more effective antitumor agents against GBM. The chemical structures of novel cinnamoyl derivatives (3a-i and 4a-i) were confirmed by NMR and MS analyses. The physicochemical properties and evaluation of the ADME profile of 3a-i and 4a-i were performed by the preADMETlab2.0 web program. Cinnamoyl derivatives 3a-i and 4a-i were tested in vitro for their cytotoxicity against the human healthy fibroblast (HDFa) cells using an MTT cell viability assay. Derivatives with no toxicity on HDFa cells were tested both on human glioblastoma (U87MG) and neuroblastoma (SHSY- 5Y) cells, chosen as an experimental model of brain tumors. Cell death mechanisms were analyzed by performing flow cytometry analyses. Cinnamoyl derivatives 3a-i and 4a-i showed good physicochemical and ADME properties suggesting that these compounds could be developed as oral drugs endowed with a high capability to cross the blood-brain barrier. Compounds (E)-1-methoxy-4-(2-(phenylsulfonyl)vinyl)benzene (2c) and (E)-N-benzyl-N-(2- (cyclohexylamino)-2-oxoethyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (3e) did not show cytotoxicity on healthy human fibroblast cells up to 100 μg/mL. The most anticarcinogenic molecule, compound 3e, emerged as the most potent anticancer candidate in this study. Flow cytometry results showed that compound 3e (25 μg/mL) application resulted in nearly 86% and 84% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. Compound 2c (25 μg/mL) resulted in 81% and 82% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. Cinnamoyl derivative 3e inhibits the proliferation of cultured U87MG and SHSY-5Y cells by inducing apoptosis. Further detailed research will be conducted to confirm these data in in vivo experimental animal models.

Antibiofilm and Antivirulence Properties of 6-Polyaminosteroid Derivatives against Antibiotic-Resistant Bacteria.

The emergence of multi-drug resistant pathogens is a major public health problem, leading us to rethink and innovate our bacterial control strategies. Here, we explore the antibiofilm and antivirulence activities of nineteen 6-polyaminosterol derivatives (squalamine-based), presenting a modulation of their polyamine side chain on four major pathogens, i.e., carbapenem-resistant A. baumannii (CRAB) and P. aeruginosa (CRPA), methicillin-resistant S. aureus (MRSA), and vancomycin-resistant E. faecium (VRE) strains. We screened the effect of these derivatives on biofilm formation and eradication. Derivatives 4e (for CRAB, VRE, and MRSA) and 4f (for all the strains) were the most potent ones and displayed activities as good as those of conventional antibiotics. We also identified 11 compounds able to decrease by more than 40% the production of pyocyanin, a major virulence factor of P. aeruginosa. We demonstrated that 4f treatment acts against bacterial infections in Galleria mellonella and significantly prolonged larvae survival (from 50% to 80%) after 24 h of CRAB, VRE, and MRSA infections. As shown by proteomic studies, 4f triggered distinct cellular responses depending on the bacterial species but essentially linked to cell envelope. Its interesting antibiofilm and antivirulence properties make it a promising a candidate for use in therapeutics.

Exploring antibiofilm potential of some new imidazole analogs against C. albicans: synthesis, antifungal activity, molecular docking and molecular dynamics studies

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins–ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb’s free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein. Communicated by Ramaswamy H. Sarma

Design, synthesis, and molecular docking studies of new phenanthrene-linked oxadiazoles as potential antimicrobial agents

Oxadiazoles and phenanthrene-based tylophorine alkaloids exhibit diverse biological activities, and the combination of both provides significant biological activity. Herein, we report the novel synthesis of phenanthrene-linked oxadiazoles (7a-m). Molecular docking studies were performed, and the binding energy values with the protein β-ketoacyl-acyl carrier protein synthase III (FabH) enzyme provide an attractive new target for the development of antibacterial agents and support their biological activities. Most of the derived compounds adhere to "Lipinski's Rule of Five" for assessing drug-likeness. The newly synthesized analogues were assessed for their in vitro antibacterial and antifungal activities against selected gram-positive and gram-negative bacteria as well as fungal strains. Compounds 7b, 7e, 7j, and 7c demonstrate potential antimicrobial activity, while the remaining compounds show moderate activity. The selected derivatives (7b, 7e, 7j, and 7c) exhibit a promising zone of inhibition (mm) against the minimum inhibitory concentration.

Vetting of New 2,5-Bis (2,2,2-trifluoroethoxy) Phenyl-Linked 1,3-Thiazolidine-4-one Derivatives as AURKA and VEGFR-2 Inhibitor Antiglioma Agents Assisted with In Vitro and In Silico Studies.

The bioactivity of 1,3-thiazolidin-4-one derivatives with a 2,5-bis (2,2,2-trifluoroethoxy) phenyl moiety was computationally developed and evaluated. All of the synthesized thiazolidin-4-one derivatives have their chemical structures characterized using a variety of methods, including nuclear magnetic resonance (NMR) (1H and 13C), high-resolution mass spectrometry (HRMS), and Fourier transform infrared (FTIR) radiation. A human glioblastoma cancer cell line (LN229) was used to investigate the purified derivatives' antiglioma cancer efficacy. By using the MTT, colony formation, and tunnel tests, respectively, the in vitro cytotoxic and apoptotic effects of these compounds were assessed. Thiazolidin-4-one derivatives 5b, 5c, and 5e were discovered to have the best efficacy against glioblastoma cells out of all of these compounds. The derivatives 5b, 5c, and 5e were determined to have respective IC50 values of 9.48, 12.16, and 6.43 g/mL. Computation results showed that the bioactivity evaluations of the compounds were quite significant. The bridging -NH group forms a hydrogen bond with Glu 260 of synthesized derivatives 5b, 5c, 5d, 5e, and 5h. The vast majority of freshly developed compounds obeyed Lipinski's rule of five, which is in line with the results that the ADMET model predicted. Additionally, molecular docking evaluation and molecular dynamics simulation investigations against the proteins AURKA and VEGFR-2 were conducted for the synthesized compounds to incorporate both in silico and in vitro data. The findings revealed that almost all of the compounds had considerable binding to AURKA and VEGFR-2 residues, with binding affinities ranging from -9.8 to -7.9 kcal/mol. Consequently, the results of the biological investigations and the docking scores demonstrated that thiazolidinone molecule 5e containing 4-chlorophenyl substituent may be considered as a potential moiety for glioblastoma cancer treatments.

2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies.

The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation

Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G0-G1 with compound 6e induced cell cycle arrest at G2M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131I-congener (131I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity.

Identification of 3-(5-cyano-6-oxo-pyridin-2-yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity.

New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.

Synthesis, biological evaluations and in silico studies on pyrimidine-appended fused pyrazolones as anticancer and antimicrobial agents

A series of twenty-two new pyrimidine appended fused pyrazolones 6a‒k and 7a‒k has been efficiently synthesized in good yields. Their structural characterization was achieved by physical and spectral analysis data (FTIR, NMR (1H & 13C), 2D NMR and HRMS) and single-crystal X-ray crystallography. All compounds were assayed for their in vitro anticancer activity against three human cancer cell lines viz. (i) human colorectal carcinoma (HCT116), (ii) human breast carcinoma (MCF7), and (iii) human prostate cancer (PC3) employing sulphorhodamine B assay by taking Camptothecin as a standard reference drug, and were also evaluated for their in vitro antimicrobial activities against two Gram-positive bacterial strains viz. E. faecalis (MTCC 439) and S. aureus (NDRI 110), two Gram-negative bacterial strains viz. E. coli (MTCC 723) and S. Typhi (MTCC 3224), and one fungal strain R. oryzae (MTCC 262) employing a quantitative micro-spectrophotometric assay by taking Tetracycline and Fluconazole as standard reference drugs for the antibacterial and antifungal testing, respectively. Amongst all the newly synthesized pyrazolones, 6e and 6j were found to exhibit maximal inhibitory activity against all the tested cancer cell lines, however, these are well active in comparison to the standard drug Camptothecin. The antimicrobial activity evaluation results revealed that compound 6k showed the highest potency against all the bacterial and fungal strains under study in comparison to the respective standard drugs Tetracycline and Fluconazole. Furthermore, in vitro anticancer activity was supported by docking studies performed on the derivatives 6e and 6j with their binding scores ‒65.842 and ‒64.555, respectively whereas the binding score of co-crystallized Topotecan was ‒65.675. Using X-ray crystal structure of compound 6e, DFT analysis gave energies of HOMO and LUMO as ‒0.2268 a.u.and ‒0.0872 a.u., respectively while the calculated dipole moment was 9.202833 D. The HOMO is mainly concentrated on chlorophenyl and indenopyrazolone nucleus while LUMO showed larger coefficient on dimethylpyrimidine ring which is in accord with binding interaction results of docking studies.

DNA major versus minor groove occupancy of monomeric and dimeric crystal violet derivatives. Toward structural correlations

Six monomeric (1a-1f) and five dimeric (2a-2e) derivatives of the triphenylmethane dye crystal violet (CV) have been prepared. Evaluation of the binding of these compounds to CT DNA by competitive fluorescent intercalator displacement (FID) assays, viscosity experiments, and UV and CD spectroscopy suggest that monomeric derivative 1a and dimeric derivative 2d likely associate with the major groove of DNA, while dimeric derivatives 2a and 2e likely associate with the minor groove of DNA. Additional evidence for the groove occupancy assignments of these derivatives was obtained from ITC experiments and from differential inhibition of DNA cleavage by the major groove binding restriction enzyme BamHI, as revealed by agarose gel electrophoresis. The data indicate that major groove ligands may be optimally constructed from dye units containing a sterically bulky 3,5-dimethyl-N,N-dimethylaniline group; furthermore, the groove-selectivity of olefin-tethered dimer 2d suggests that stereoelectronic interactions (n → π*) between the ligand and DNA are also an important design consideration in the crafting of major-groove binding ligands.