Compounds 4j Research Articles

Design, synthesis, and mechanistic evaluation of novel benzimidazole-hydrazone compounds as dual inhibitors of EGFR and HER2: Promising candidates for anticancer therapy

A series of twelve benzimidazole-hydrazone compounds were synthesized and evaluated for their cytotoxicity on three cancer cell lines (HepG-2, MCF-7, and HCT-116) using the MTT assay. The compounds' IC50 values were compared to the anticancer drug sunitinib. Additionally, we investigated the dual inhibition of compounds 6e and 6j on EGFR and HER2 tyrosine kinase enzymes. Flow cytometry analysis revealed that compound 6e induced cell cycle arrest and apoptosis in HepG-2 cells. Molecular docking analysis showed that compound 6e interacted with the ATP binding pocket of EGFR and HER2, exhibiting hydrophobic interactions and distinct hydrogen bonding patterns. Notably, compounds 6e, 6g, 6h, 6j, and 6l exhibited potent cytotoxicity comparable to sunitinib against all tested cancer cell lines. Compound 6e demonstrated dual inhibition of EGFR and HER2 and displayed favorable druglike properties. These findings suggest that compound 6e has potential as a lead compound for targeting the EGFR and HER2 pathways and warrant further optimization and development as a potential anticancer therapeutic agent.

Dimeric peptoids as antibacterial agents

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 μg mL−1 and 6.2 μg mL−1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 μg mL−1 and 11.2 μg mL−1) and 56 %-58 % at 8x MIC (MIC = 35.2 μg mL−1 and 22.4 μg mL−1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Molecular Docking, Toxicity Study and Antimicrobial Assessment of Novel Synthesized 1,3-(Disubstituted)-thiazol-2-amines

In current study, a novel analogous of substituted-2-aminothiazoles (3a-o) were synthesized through a multi-step synthetic process. Structural elucidation of these newly synthesized substituted-2-aminothiazoles were achieved using combination of analytical techniques, comprising proton nuclear magnetic resonance (PNMR), mass spectrometry and FTIR. An in vitro investigation was performed to measure the efficacy of antibacterial and antimycotic characteristics of these novel compounds (3a-o). Specifically, the growth-inhibiting action against the test fungal strains, including A. niger, M. purpureos and A. flavus was examined. Additionally, their inhibitory antibacterial activity against key bacterial strains, including P. aeruginosa, S. aureus and E. coli was ascertained employing the agar diffusion technique. The results of antibacterial screening disclosed that maximum number of the thiazole derivatives viz. 3a, 3d, 3e, 3i, 3k, 3l and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for E. coli. While compounds 3k and 3n displayed minimum inhibitory concentration of 12.5 µg/mL for S. aureus. A minimum inhibitory concentration of 25 µg/mL was exhibited by compounds 3i, 3l and 3n against P. aeruginosa. None of the 2-aminothiazole derivative disclosed promising action against the fungal strains. Screening for in silico ADME and toxicity studies revealed that compounds are fairly compatible and were devoid of potential toxicity except compounds 3j and 3m. The docking studies on DNA gyrase (PDB ID; 1KZN) shows favourable binding interaction comparable to the pre-occupied ligand clorobiocin.

Synthesis, Anticancer Evaluation and Molecular Docking Studies of 1-(2-Fluorobenzyl)piperazine Triazoles: A Novel Breast Cancer Cell Inhibitors

New series of 1-(2-fluorobenzyl)piperazine triazoles 7(a-k) have been synthesized and evaluated for anticancer activity. The molecular structures of all the compounds were established by employing 1H NMR, 13C NMR and mass spectral analysis. In vitro anticancer activity was evaluated using MTT assay against MCF7 breast cancer cell line. Compounds 7i and 7j bearing 4-fluorophenyl and 2-fluorophenyl pendant from triazole substituent phenyl ring exhibited the highest anticancer efficacy with IC50 values of 12.09 µg/mL and 15.12 µg/mL, respectively. A molecular docking study conducted on human HER2 complexed with hercepatin fab was acquired from Protein Data Bank (PDB ID: 1N8Z). Molecular docking studies demonstrated Leu443, Gly442 and Leu27 as key residues interacting with active compounds.

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazole derivatives from benzo hydrazide and amino acids as novel potential antioxidant and antibacterial agents have been reported. The structures of the new compounds were characterized by physicochemical properties and spectral methods. The synthesized compounds were screened for their in vitro antibacterial activity against three Gram-positive bacterial strains, namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and two Gram-negative bacterial strains, namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and antifungal activity against Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline, Gentamicin and Oxacillin as standards. Most of the compounds have excellent efficacy, and some of them, such as 5i, 5g, 5d, 5c, and 5j can inhibit their activity better or very close to that of Amoxicillin, Tetracycline, Gentamicin, Oxacillin used as standards. Compounds 5b and 5i provided good results against L. innocua with inhibition values of IZ = 14 mm and IZ = 22 mm, respectively, while the rest of the compounds and antibiotics were unable to inhibit it. Compounds 5c, 5d, 5g and 5j showed excellent activity against C. albicans with values between 31 mm and 34 mm. These results were better than all the standards used. The MIC value (25 µg/ml) for derivatives 5(c-e), 5g and 5(i-j) against B. cereus represent the best activity of the tested compounds. All the target compounds were also screened for radical scavenging antioxidant activities by DPPH, FRAP, and TAC assays and found to be excellent antioxidant agents. According to the results, it was observed that most derivatives synthesized showed excellent activity with a concentration of 250 µg/ml as an antioxidant agent (76 % < RSA < 95.5 %) which gave an inhibition percentage that was better or very close to that of ascorbic acid and better than BHT.

Synthesis, biological evaluation and in-silico ADMET studies of novel chalcones and dihydro pyrazoles of 2H-Chromene as anticancer agents

2H-chromenes and chalcones are biologically important scaffolds with applications in drug discovery. Their ease of synthesis and biological importance have attracted the attention of medicinal chemists worldwide. Inspired by this, we synthesized various substituted chalcones and dihydropyrazole derivatives bearing various aryl and hetero-aryl 2H-chromene moieties. The resulting compounds were evaluated for cytotoxicity in vitro against doxorubicin in triple-negative breast cancer cell lines (MDA-MB-231), estrogen receptor-positive breast cancer cell lines (MCF-7), and human brain glioblastoma (U-87 MG) cell lines. Compounds 6b and 6j exhibited anticancer activity against triple-negative breast cancer cell line (MDA-MB-231), with IC50 values of 4.02 µM and 3.35 µM, respectively. Further investigation involving in silico pharmacokinetic (ADME) and toxicity studies also revealed pivotal features for the favourable bioavailability of these derivatives.

Antioxidant and antibacterial activities of 5-mercapto(substitutedthio)-4-substituted-1,2,4-triazol based on nalidixic acid: A comprehensive study on its synthesis, characterization, and In silico evaluation

This study introduces a series of novel Alkyl thio-1,2,4-triazole (4a-p) and mercapto-1,2,4-triazole (3a-d) compounds derived from nalidixic acid. The synthesis was streamlined, involving interactions between nalidixic acid hydrazide and various isothiocyanates to yield cyclic and alkyl(aryl) sulfide compounds, characterized using 1H NMR, 13C NMR, IR, and elemental analysis. Antioxidant capabilities were quantified through DPPH and ABTS assays, highlighting significant potential, especially for compound 3d, which demonstrated an ABTS IC50 value of 0.397 μM, on par with ascorbic acid (IC50 = 0.87 μM). Antibacterial efficacy was established through MIC assessments against a broad spectrum of Gram-positive and Gram-negative bacteria, including Candida albicans. Compounds 3b, 4e, 4h, 4j, 4i, 4m, and 4o showed broad-spectrum activity, with 4k and 4m exhibiting pronounced potency against E. coli. Molecular docking studies validated the antibacterial potential, with compounds 4f and 4h showing high binding affinities (docking scores of −9.8 and −9.6 kcal/mol, respectively), indicating robust interactions with the bacterial enzyme targets. These scores underscore the compounds' mechanistic basis for their antibacterial action and support their therapeutic promise. Furthermore, compounds 3b, 4i, and 4m, identified through drug-likeness and toxicity predictions, were highlighted for their favorable profiles, suggesting their suitability for oral antibiotic therapies. This comprehensive study, blending synthetic, in vitro, and in silico approaches, emphasizes the triazole derivatives' potential as future candidates for antibiotic and antioxidant applications, particularly spotlighting compounds 3b, 4i, and 4m due to their promising efficacy and safety profiles.

Design, synthesis and anti-oomycete activity of 2-acyloxyhinokitiol derivatives

In order to explore novel natural product-based anti-oomycete agent, ten 2-acyloxyhinokitiol derivatives (5a–j) were designed and synthesised, and structurally confirmed by 1H NMR,13C NMR, HRMS, and melting point. The stereochemical configuration of compound 5f was unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we evaluated the target compounds 5a–j as anti-oomycete activity against a serious agricultural disease of Phytophthora capsici. Among the ten hinokitiol ester derivatives tested, four compounds 5d, 5g, 5h and 5j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 23.59 mg/L), and the EC50 values of 18.90, 20.62, 13.61 and 21.29 mg/L, respectively. Especially compound 5h exhibited the best anti-oomycete activity against P. capsici with EC50 value of 13.61 mg/L. Overall, the anti-oomycete activities of 2-acyloxyhinokitiol derivatives is higher than that of 2-sulfonyloxyhinokitiol derivatives. The results laid a good foundation for the subsequent synthesis of hinokitiol ester derivatives with significant anti-oomycete activity.

Synthesis, biological evaluation and molecular docking study of pyrimidine linked thiazolidinedione derivatives as potential antimicrobial and antitubercular agents

The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g, 5i, and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus, respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g, 5i, and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g, 5i, and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g, 5i, and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g, 5i, and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents.

Novel [1,3,4]Thiadiazole[3,2-a]pyrimidin-5-ones as Promising Biofilm Dispersal Agents against Relevant Gram-Positive and Gram-Negative Pathogens.

Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC50 values ranging from 17 to 40 µg/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections.

Green Method Synthesis of Magnetic Nanoparticles and its Functionalized MNPs for Knoevenagel Condensation Reaction

Background: Knoevenagel condensation is an important C-C bond formation reaction catalyzed by various homogeneous and heterogeneous acid-base catalysts. background: Knoevenagel condensation is an important C-C bond formation reaction, and employs various acid and base-catalyzed reactions of both homogeneous and heterogeneous catalysts. Method: The present work describes the eco-friendly preparation of magnetic nanoparticles Fe3O4 (MNPs) and its functionalization to Fe3O4@SiO2@SO3H. The prepared MNPs and their functionalized materials were fully characterized by FT-IR, XRD, FE-SEM, HR-TEM, and VSM. Further demonstrated application of these catalysts for the C-C bond formation reactions of Knoevenagel condensation employing special aldehyde derivatives with malononitrile at room temperature gave excellent product isolation. Results: The application of the prepared functionalized MNPs for the Knoevenagel condensation was demonstrated by the reaction of various aryl/heterocyclic and cholesterol aldehyde with malononitrile at room temperature stirring for about 30 min in ethanol solvent. The final product isolated is confirmed by various spectroscopic techniques such as FT-IR, 1H-, &amp; 13C-NMR, and mass spectrometry. Furthermore, the selected compounds are screened for their photophysical properties, and interestingly compound 3j showed good fluorescent properties. Conclusion: Overall the present work described a greener method preparation of MNPs, and its functionalized employed as a heterogeneous catalyst for the Knoevenagel condensation of various aryl/heterocyclic and cholesterol aldehyde with malononitrile. The method developed is simple, easily separated catalyst by an external magnet, and recycled up to five cycles without any noticeable change in the final product isolation. Further, the prepared derivatives screened for their photophysical properties, and interestingly compound 3j showed good fluorescent properties.

In vitro anti-Helicobacter pylori, anti-urease and anti-gastric cancer activities of novel hydrazones

In this study, new hydrazone derivatives were synthesized by taking into account the virulence factor of the urease in the urease-positive microorganism H. pylori. The structure of synthesized compounds 3a-3j was confirmed using 1H NMR, 13C NMR and elemental analyses. After structure confirmations all compounds were evaluated for in vitro urease inhibitory and anti-H. pylori activities. Furthermore, since H. pylori infection is associated with gastric cancer, the effects of the synthesized compounds against two different gastric cancer cell lines (SNU1 and AGS) were also evaluated. Amongst the series, two compounds 3c and 3j were found to be excellent inhibitors of urease, having IC50 values of 9.813 ± 0.403 µM and 11.407 ± 0.393 µM, better than the standard thiourea (IC50 = 13.428 ± 0.587 µM), whereas the remaining compounds displayed moderate activity. Compounds 3c and 3d were found to be the most active in the series against H. pylori with MIC values 4 µg/mL and 5 µg/mL. Next, compounds were evaluated as anti-gastric cancer activity and the compounds 3c and 3j were more potent than reference drug cisplatin against SNU1 and AGS. The docking study was executed to analyzed the interaction between the active site of the urease and the compounds 3c and 3j. When the all activities (anti-H. pylori, anti-urease and anti-gastric cancer activities) examined, it was found that the presence of the nitro group, which is an electron withdrawing group, in the 5th position of the thiophene ring (compound 3c) increased all activities. From the structure-activity relationship, it has been observed that the compound 3c showed excellent potential for anti-H. pylori, anti-gastric cancer and can be alternative therapy in the future.

Sulfonyl thiourea derivatives from 2-aminodiarylpyrimidines: Invitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors.

A series of synthesized sulfonyl thiourea derivatives (7a-o) of substituted 2-amino-4,6-diarylpyrimidines (4a-o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by invitro enzymatic assays. 7a (KI = 46.14 nM), 7j (KI = 48.92 nM), and 7m (KI = 62.59 nM) (for isoform hCA I); 7f (KI = 42.72 nM), 7i (KI = 40.98 nM), and 7j (KI = 33.40 nM) (for isoform hCA II); 7j (KI = 228.5 nM), 7m (KI = 195.4 nM), and 7n (KI = 210.1 nM) (for isoform hCA IX); 7l (KI = 116.9 nM), 7m (KI = 118.8 nM), and 7n (KI = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor-associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of invitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.

Synthesis of Piperidine Conjugated Quinoxalines as Potential Antibiofilm Agents

Background: The most common cause of food-borne illness is bacterial or viral contamination. Although there are several therapeutics available to combat these microbes, they lost their efficacy in long-term medication. Because, over a period of time, microbes developed resistance against drugs and this antimicrobial resistance is a serious threat to global public health as a consequence of the widely disseminated and careless use of antimicrobials. Therefore, there is a need to develop some new chemical moieties with a safety factor and better efficacy. A series of substituted N-(1-benzylpiperidin-4- yl)quinoxalin-2-amines (5a-j) (5ab, 5ac) were synthesized and screened for their in vitro antibacterial activity against Salmonella paratyphi, a well-known food-borne pathogen. Methods: Experimental methods, agar diffusion and broth microdilution assays were carried out to evaluate the antibacterial activity of the lead compounds. Further, antibiofilm methods, crystal violet, and MTT assays were subjected to investigate their biofilm inhibition capacity against S. paratyphi. Results: Among the tested compounds, 5b, 5e, 5h, and 5j bearing 4-chloro, 3,4-dimethoxy, 4-methyl and thienyl groups on the phenyl ring of quinoxalines emerged as potential candidates having significant antisalmonella activity. In these four potential candidates, compounds 5b and 5h were effective against Salmonella whereas compounds 5e and 5j effectively inhibited the biofilm formation of Salmonella. Conclusion: N-(1-benzylpiperidin-4-yl)quinoxalin-2-amines (5a-j) (5ab, 5ac) were synthesized and evaluated for antisalmonella activity against S. paratyphi. Among the series of compounds, four compounds significantly showed good activity and emerged as antibacterial agents for further studies in the future.

Development of Novel Indazolyl-Acyl Hydrazones as Antioxidant and Anticancer Agents that Target VEGFR-2 in Human Breast Cancer Cells.

The increased expression of VEGFR-2 in a variety of cancer cells promotes a cascade of cellular responses that improve cell survival, growth, and proliferation. Heterocycles are common structural elements in medicinal chemistry and commercially available medications that target several biological pathways and induce cell death in cancer cells. Herein, the evaluation of indazolyl-acyl hydrazones as antioxidant and anticancer agents is reported. Compounds 4e and 4j showed inhibitory activity in free radical scavenging assays (DPPH and FRPA). The titled compounds were employed in cell viability studies using MCF-7 cells, and it was observed that compounds 4f and 4j exhibited IC50 values 15.83 μM and 5.72 μM, respectively. In silico docking revealed the favorable binding energies of -7.30 kcal/mol and -8.04 kcal/mol for these compounds towards Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), respectively. In conclusion, compounds with antioxidant activity and that target VEGFR-2 in breast cancer cells are reported.

Eugenol derivatives containing 1,2,3-triazole-chalcone hybrids for shikimate kinase inhibition

Eugenol, a primary component of clove oil, is a compound of considerable interest in medicinal chemistry due to its demonstrated potential as an effective agent in various therapeutic applications. In this study, a series of eugenol derivatives were designed and synthesized based on the hybridization of eugenol with 1,2,3-triazole and chalcone moieties. Compound 5j and 5k were denoted as lead structures against Mycobacterium tuberculosis Shikimate Kinase (MtSK). Moreover, the docking studies indicated that both the eugenol and triazole fragments in compound 5j and 5k played a pivotal role in the inhibition activity of MtSK, owing to their binding interactions with Arg58, Pro118, and Arg136 residues. Furthermore, in silico drug-likeness prediction analysis suggested that the majority of the synthesized compounds exhibit good oral bioavailability based on their molecular properties and Lipinski’s Rule of Five predictions.

Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors

A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew’s correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.

Design, synthesis and evaluation of aminothiazole derivatives as potential anti-Alzheimer's candidates.

Aim: The objective of the present study was to design, synthesize and evaluate diverse Schiff bases and thiazolidin-4-one derivatives of aminothiazole as key pharmacophores possessing acetylcholinesterase inhibitory activity. Materials & methods: Two series of compounds (13 each) were synthesized and evaluated for their acetylcholinesterase inhibition and antioxidant activity. Molecular docking of all compounds was performed to provide an insight into their binding interactions. Results: Compounds 2j (IC50=0.03μM) and 3e (IC50=1.58μM) were found to be the best acetylcholinesterase inhibitors among compounds of their respective series. Molecular docking analysis supported the results of in vitro activity by displaying good docking scores with the binding pocket of human acetylcholinesterase (ProteinData Bank ID: 4EY7). Conclusion: Compound 2j emerged as a potential lead compound with excellent acetylcholinesterase inhibition, antioxidant and chelation activity.

Design, Synthesis, and Antifungal/Anti-Oomycete Activities of Novel 1,2,4-Triazole Derivatives Containing Carboxamide Fragments.

Plant diseases caused by pathogenic fungi or oomycetes seriously affect crop growth and the quality and yield of products. A series of novel 1,2,4-triazole derivatives containing carboxamide fragments based on amide fragments widely used in fungicides and the commercialized mefentrifluconazole were designed and synthesized. Their antifungal activities were evaluated against seven kinds of phytopathogenic fungi/oomycete. Results showed that most compounds had similar or better antifungal activities compared to mefentrifluconazole's inhibitory activity against Physalospora piricola, especially compound 6h (92%), which possessed outstanding activity. Compound 6h (EC50 = 13.095 μg/mL) showed a better effect than that of mefentrifluconazole (EC50 = 39.516 μg/mL). Compound 5j (90%) displayed outstanding anti-oomycete activity against Phytophthora capsici, with an EC50 value of 17.362 μg/mL, far superior to that of mefentrifluconazole (EC50 = 75.433 μg/mL). The result of molecular docking showed that compounds 5j and 6h possessed a stronger affinity for 14α-demethylase (CYP51). This study provides a new approach to expanding the fungicidal spectrum of 1,2,4-triazole derivatives.