Biologically Potent Benzimidazole-Based-Substituted Benzaldehyde Derivatives as Potent Inhibitors for Alzheimer's Disease along with Molecular Docking Study.

Twenty-one analogs were synthesized based on benzimidazole, incorporating a substituted benzaldehyde moiety (1-21). These were then screened for their acetylcholinesterase and butyrylcholinesterase inhibition profiles. All the derivatives except 13, 14, and 20 showed various inhibitory potentials, ranging from IC50 values of 0.050 ± 0.001 µM to 25.30 ± 0.40 µM against acetylcholinesterase, and 0.080 ± 0.001 µM to 25.80 ± 0.40 µM against butyrylcholinesterase, when compared with the standard drug donepezil (0.016 ± 0.12 µM and 0.30 ± 0.010 µM, against acetylcholinesterase and butyrylcholinesterase, respectively). Compound 3 in both cases was found to be the most potent compound due to the presence of chloro groups at the 3 and 4 positions of the phenyl ring. A structure-activity relationship study was performed for all the analogs except 13, 14, and 20, further, molecular dynamics simulations were performed for the top two compounds as well as the reference compound in a complex with acetylcholinesterase and butyrylcholinesterase. The molecular dynamics simulation analysis revealed that compound 3 formed the most stable complex with both acetylcholinesterase and butyrylcholinesterase, followed by compound 10. As compared to the standard inhibitor donepezil both compounds revealed greater stabilities and higher binding affinities for both acetylcholinesterase and butyrylcholinesterase.

N-([1,1'-biaryl]-4-yl)-1-naphthamide-based scaffolds synthesis, their cheminformatics analyses, and screening as bacterial biofilm inhibitor.

Naphthamides have pharmacological potential as they express strong activities against microorganisms. The commercially available naphthoyl chloride and 4-bromoaniline were condensed in dry dichloromethane (DCM) in the presence of Et3 N to form N-(4-bromophenyl)-1-naphthamide (86%) (3). Using a Pd(0) catalyzed Suzuki-Miyaura Cross-Coupling reaction of (3) and various boronic acids, a series of N-([1,1'-biaryl]-4-yl)-1-naphthamide derivatives (4a-h) were synthesized in moderate to good yields. The synthesized derivatives were evaluated for cytotoxicity haemolytic assay and biofilm inhibition activity through in silico and in vitro studies. Molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity risk, and other cheminformatics predict synthesized molecules as biologically active moieties, further validated through in vitro studies in which compounds (4c) and (4f) showed significant haemolytic activity whereas (4e) exhibited an efficient biofilm inhibition activity against Gram-negative bacteria Escherichia coli and Gram-positive bacteria Bacillus subtilis. When forming biofilms, bacteria become resistant to various antimicrobial treatments. Currently, research is focused on the development of agents that inhibit biofilm formation, thus the present work is valuable for preventing future drug resistance.

Bi-heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches.

Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a-k) with 4-(chloromethyl)benzoylchloride (6) to afford 4-(chloromethyl)-N-(substituted-phenyl)benzamides (7a-k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a-k, to acquire the targeted bi-heterocyclic benzamides, 8a-k. The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI-MS, and CHN analysis data. The inhibitory effects of these bi-heterocyclic benzamides (8a-k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver-Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 µM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.

2-Mercaptobenzimidazole Schiff Bases: Design, Synthesis, Antimicrobial Studies and Anticancer Activity on HCT-116 Cell Line.

BACKGROUND: Increased rate of mortality due to the development of resistance to currently available antimicrobial and anticancer agents initiated the need to develop new chemical entities for the treatment of microbial infections and cancer. OBJECTIVE: The present study was aimed to synthesize and evaluate antimicrobial and anticancer activities of Schiff bases of 2-mercaptobenzimidazole. METHODS: The Schiff bases of 2-mercaptobenzimidazole were synthesized from 4-(2-(1H-benzo[d]- imidazol-2-ylthio)acetamido)benzohydrazide. The synthesized compounds were evaluated for antimicrobial and anticancer activities by tube dilution method and Sulforhodamine-B (SRB) assay, respectively. RESULTS: Compounds 8 (MICpa, an = 2.41, 1.20 µM/ml), 10 (MICse, sa = 2.50 µM/ml), 20 (MICec = 2.34 µM/ml) and 25 (MICca = 1.46 µM/ml) showed significant antimicrobial activity against tested bacterial and fungal strains and compounds 20 (IC50 = 8 µg/ml) and 23 (IC50 = 7 µg/ml) exhibited significant anticancer activity. CONCLUSION: In general, the synthesized derivatives exhibited moderate antimicrobial and anticancer activities. Compounds 8 and 25 having high antifungal potential among the synthesized compounds may be taken as lead molecules for the development of novel antifungal agents.

Fusing Results of Several Deep Learning Architectures for Automatic Classification of Normal and Diabetic Macular Edema in Optical Coherence Tomography.

Diabetic Macular Edema (DME) is a severe eye disease that can lead to irreversible blindness if it is left untreated. DME diagnosis still relies on manual evaluation from opthalmologists, thus the process is time consuming and diagnosis may be subjective. This paper presents two novel DME detection frameworks: (1) combining features from three pre-trained Convolutional Neural Networks: AlexNet, VggNet and GoogleNet and performing feature space reduction using Principal Component Analysis and (2) a majority voting scheme based on a plurality rule between classifications from AlexNet, VggNet and GoogleNet. Experiments were conducted using Optical Coherence Tomography datasets retrieved from the Singapore Eye Research Institute and the Chinese University Hong Kong. The results are evaluated using a Leave-Two-Patients-Out Cross Validation at the volume level. This method improves DME classification with an accuracy of 93.75%, which is similar to the best algorithms so far on the same data sets.

Novel Cyclopentadienyl-Free Organolanthanides: The First Examples of Five-Membered Amidolanthanide Heterocycles.

Reactions of LnCl(3) (Ln = Nd, Gd, Yb) and [{Me(2)SiN(R)Li}(2)] (R = t-Bu, Ph) give the chloride-bridged dimers [{{(t-Bu)NSiMe(2)SiMe(2)N(t-Bu)}Ln(&mgr;-Cl)(THF)}(2)] (1, Ln = Nd; 2, Ln = Gd; 3, Ln = Yb) and [{{(Ph)NSiMe(2)SiMe(2)N(Ph)}Ln(&mgr;-Cl)(THF)(2)}(2)] (4, Ln = Nd; 5, Ln = Gd; 6, Ln = Yb) in good yields. Compounds 2 and 5 were structurally characterized by X-ray crystallography: 2, triclinic, P&onemacr;, a = 10.321(2) Å, b = 11.116(2) Å, c = 13.434(3) Å, alpha = 107.57(3) degrees, beta = 111.31(3) degrees, gamma = 90.67(3) degrees, V = 1356.1(5) Å(3), Z = 1, R = 0.0233; 5, monoclinic, P2(1)/n, a = 13.913(13) Å, b = 12.914(9) Å, c = 16.434(14) Å, beta = 105.64(3) degrees, V = 2843(4) Å(3), Z = 2, R = 0.0281. The chloro functions in 1-6 remain reactive, demonstrated by the isolation of the trifluoroacetate derivatives of 1 and 2. Treatment of 1 or 2 with 2 equiv of NaOCOCF(3) gives [{{(t-Bu)NSiMe(2)SiMe(2)N(t-Bu)}Ln(&mgr;-OCOCF(3))(THF)}(2)] (7, Ln = Nd; 8, Ln = Gd). The structure of 8 was determined by a single-crystal X-ray diffraction analysis. Crystal data for 8: triclinic, P&onemacr;, a = 11.045(2) Å, b = 16.120(3) Å, c = 16.949(3) Å, alpha = 66.17(3) degrees, beta = 85.51(3) degrees, gamma = 78.27(3) degrees, V = 2702.9(9) Å(3), Z = 2, R = 0.0311. The structure of 8 shows the trifluoroacetate group adopting a bridging bidentate mode of coordination.

Organometallic Fluorides of Zirconium and Hafnium in the Synthesis of Carboxylate Complexes: Molecular Structures of [{(eta(5)-C(5)Me(5))ZrF(OCOCF(3))(2)}(2)] and [(eta(5)-C(5)Me(5))(2)Zr(OCOCF(3))(2)].

The reaction of [(eta(5)-C(5)Me(5))ZrF(3)] and [(eta(5)-C(5)Me(5))HfF(3)] with Me(3)SiOCOCF(3) yields the dinuclear complexes [{(eta(5)-C(5)Me(5))ZrF(OCOCF(3))(2)}(2)] (1) and [{(eta(5)-C(5)Me(5))HfF(OCOCF(3))(2)}(2)] (2), regardless of the molar ratio employed. [(eta(5)-C(5)Me(5))(2)ZrF(2)] reacts with 1 and 2 equiv of Me(3)SiOCOCF(3) to form the mononuclear compounds [(eta(5)-C(5)Me(5))(2)Zr(OCOCF(3))(2)] (3) and [(eta(5)-C(5)Me(5))(2)ZrF(OCOCF(3))] (4), respectively. The molecular structures of 1 and 3 have been determined by single-crystal X-ray analysis: 1, triclinic, P&onemacr;, a = 9.508(3) Å, b = 11.002(4) Å, c = 17.528(3) Å, alpha = 78.55(4), beta = 76.80(2), gamma = 87.51(2) degrees, V = 1750(1) Å(3), Z = 2, R = 0.0378; 3, monoclinic, C2/c, a = 18.553(4) Å, b = 9.110(2) Å, c = 16.323(3) Å, beta = 114.88(3) degrees, V = 2503(1) Å(3), Z = 4, R = 0.0457. Compound 1 shows bridging bidentate and chelating carboxylate ligands as well as bridging fluorine atoms. The zirconium atoms are seven coordinated and have an 18-electron configuration. X-ray studies of 3 reveal two structural components where the carboxylate ligands coordinate in a monodentate (major component) and a chelating manner (minor component).