Facile synthesis and in silico studies of benzothiazole-linked hydroxypyrazolones targeting α-amylase and α-glucosidase.

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t, were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

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Design, synthesis, α-amylase and glucose diffusion inhibition, and molecular docking studies of new indenopyrazolones bearing benzothiazole derivatives.

An eco-friendly facile synthesis of a series of twenty 1-(4/6-substitutedbenzo[d]thiazol-2-yl)-3-(phenyl/substitutedphenyl)indeno[1,2-c]pyrazol-4(1H)-ones 7a-t was achieved by the reaction of 2-(benzoyl/substitutedbenzoyl)-(1H)-indene-1,3(2H)-dione 3a-t and 2-hydrazinyl-4/6-substitutedbenzo[d]thiazole 6a-t in presence of freshly dried ethanol and glacial acetic acid under reflux conditions in good yields. The newly synthesized derivatives were well characterized using different physical and spectral techniques (FTIR, 1H NMR & 13C NMR, and HRMS). All the compounds were subjected to assess their in vitro α-amylase and glucose diffusion inhibitory activity. Amongst them, the compounds 7i and 7l showed better α-amylase inhibitory activity demonstrating IC50 values of 92.99±1.94 µg/mL and 95.41±3.92 µg/mL, respectively in comparison to the standard drug acarbose (IC50 value of 103.60±2.15 µg/mL). The derivatives 7d and 7k exhibited good glucose diffusion inhibition with values of 2.25±1.16 µg/mL and 2.63±1.45 µg/mL, respectively with standard reference acarbose (2.76±0.55 µg/mL). The observed α-amylase inhibitory activity findings were corroborated through molecular docking investigations, particularly for the highly active compounds 7i (binding energy -8.0 kcal/mol) and 7l (binding energy -8.2 kcal/mol) respectively, in comparison to acarbose with a value of binding energy -6.9 kcal/mol for α-amylase.

Synthesis of Indole-Linked Thiadiazoles and their Anticancer Action against Triple-Negative Breast Cancer.

With a lack of targeted therapy and significantly high metastasis, heterogeneity, and relapse rates, Triple-Negative Breast Cancer (TNBC) offers substantial treatment challenges and demands more chemotherapeutic interventions. In the present study, indole-endowed thiadiazole derivatives have been synthesized and screened for antiproliferative potency against the triple-negative breast cancer MDA-MB-231 cell line. Compound 4 h, possessing chlorophenyl moiety, displays the best anticancer potency (IC50: 0.43 µM) in the cell viability assay. The title compounds demonstrate substantial docking competency against the EGFR receptor (PDB ID: 3POZ), validating their in-vitro ant proliferative action. With a high docking score (-9.9 to -8.7 kcal/mol), the indole hybrids display significant binding propensity comparable to the co-crystallized ligand TAK-285 and occupy a similar strategic position in the active domain of the designated receptor. The quantum and electronic properties of the integrated templates are evaluated through DFT, and optimal values of the deduced global reactivity indices, such as energy gap, electronegativity, ionization potential, chemical potential, electrophilicity, etc., suggest their apt biochemical reactivity. The indole hybrids show near-appropriate pharmacokinetic efficacy and bioavailability in the in-silico studies, indicating their candidacy for potential drug usage. Promising in-vitro anticancer action and binding interfaces project indole conjugates as potential leads in addressing the TNBC dilemma.

Convenient synthesis of benzothiazinoisoindol-11-ones and benzoindenothiazin-11-ones, and antimicrobial testing thereof.

Benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones 5a-t and benzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones 6a-e were synthesized conveniently via cyclocondensation of 2-bromo-2-(2/3-substitutedphenyl)-1H-indene-1,3(2H)-diones and 2-aminobenzenethiols in freshly dried ethanol with 70-85% yields. The synthesized derivatives were well characterized by employing different spectral techniques (FTIR, 1H & 13C NMR and HRMS) and X-ray crystallographic analysis. Further, all the reported compounds were tested for their antibacterial and antifungal activities using Ciprofloxacin and Fluconazole as standard drugs, respectively. The results of antimicrobial evaluation revealed that compounds 5o and 5t displayed remarkable inhibitory activity against B. subtilis, S. aureus, P. aeruginosa and A. niger with MIC values in the range of 0.0141-0.0283 µmol/mL, whereas 5j was found active against E. coli and C. albicans with MIC values of 0.0286 µmol/mL and 0.0143 µmol/mL, respectively. Additionally, among all the benzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones, 6c exhibited excellent inhibition against all the tested bacterial and fungal strains with MIC values ranging from 0.0143 to 0.1145 µmol/mL. Structure activity relationships were also established for all the tested benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones 5a-t.

Recent Progress in Anticancer Agents Incorporating Pyrazole Scaffold.

The search for new anticancer agents is considered a dynamic field of medicinal chemistry. In recent years, the synthesis of compounds with anticancer potential has increased and a large number of structurally varied compounds displaying potent anticancer activities have been published. Pyrazole is an important biologically active scaffold that possesses nearly all types of biological activities. The aim of this review is to collate literature work reported by researchers to provide an overview on in vivo and in vitro anticancer activities of pyrazole based derivatives among the diverse biological activities displayed by them and also to present recent efforts made on this heterocyclic moiety regarding anticancer activities. This review has been driven by the increasing number of publications on this issue, which have been reported in the literature since the end of the 20th century (from 1995-to date).

Synthesis, Type II diabetes inhibitory activity, antimicrobial evaluation and docking studies of indeno[1,2-c]pyrazol-4(1H)-ones.

We report a convenient and efficient synthesis of indeno[1,2-c]pyrazol-4(1H)-ones (4a‒o) by the reaction of a variety of 2-acyl-(1H)-indene-1,3(2H)-diones (1) and 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles (2) in the presence of glacial acetic acid in good yields. The structure of the compounds thus prepared were confirmed by analytical and spectral (FT-IR, 1H NMR, 13C NMR, and HRMS) techniques. All the synthesized indeno[1,2-c]pyrazol-4(1H)-ones (4a‒o) were assayed for their in vitro Type II diabetes inhibitory activity by using Acarbose as standard drug and in vitro antimicrobial activity utilizing Streptomycin and Fluconazole as reference drugs. Among the synthesized derivatives, 4e (IC50 = 6.71 µg/mL) was found to be more potent against α-glucosidase enzyme as compared with the standard Acarbose (IC50 = 9.35 µg/mL) and 4i (IC50 = 11.90 µg/mL) exhibited good inhibitory activity against α-amylase enzyme as compared with the standard Acarbose (IC50 = 22.87 µg/mL). Also, all the titled compounds showed good antimicrobial activity. In addition, in vitro α-glucosidase and α-amylase inhibition were supported by docking studies performed on the derivatives 4e and 4o, respectively.

Convenient and efficient synthesis of novel 11H-benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones derived from 2-bromo-(2/3-substitutedphenyl)-1H-indene-1,3(2H)-diones.

An unprecedented formation of 11H-benzo[5,6][1,4]thiazino[3,4-a]isoindol-11-ones through a one-step reaction of differently substituted 2-aminobenzenethiols and 2-bromo-(2/3-substitutedphenyl)-1H-indene-1,3(2H)-diones in freshly dried ethanol under reflux conditions has been investigated. This unique transformation probably occurs through an initial nucleophilic substitution followed by ring opening and subsequent intramolecular cyclization. The structures of all the synthesized benzo[1,4]thiazino isoindolinones were established by FTIR, 1H NMR, 13C NMR, HRMS, and X-ray crystallographic analysis. This approach was found to be simple and convenient and provides several advantages such as substantial atom economy, short reaction time and operational simplicity.

Synthesis, characterization, biological evaluation and QSAR studies of 11-p-substituted phenyl-12-phenyl-11a,12-dihydro-11H-indeno[2,1-c][1,5]benzothiazepines as potential antimicrobial agents.

A novel series of 11-p-substituted phenyl-12-phenyl-11a,12-dihydro-11H-indeno[2,1-c][1,5]benzothiazepines (3) has been synthesized and screened for their antimicrobial activity against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and fungi (Aspergillus fumigates and Candida albicans). The antimicrobial evaluation data indicated that the compounds, 3d, 3g, 3h, 3k-3p exhibited very promising antibacterial activity and the derivatives 3k, 3l, 3o and 3p exhibited high antifungal activity. The QSAR studies carried out to find out the correlation between the antimicrobial activity and physicochemical properties of synthesized benzothiazepines (3) indicated the predominance of electronic parameters in describing their antimicrobial activity.

Synthesis, characterization, antimicrobial activities and QSAR studies of some 10a-phenylbenzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones.

A series of 10a-phenylbenzo[b]indeno[1,2-e][1,4]thiazin-11(10aH)-ones (3) has been synthesized and tested for their antimicrobial activity. The antimicrobial evaluation data indicated that compounds, 3b, 3d, 3k and 3m exhibited very promising antibacterial activity and the compounds 3b and 3k exhibited notable activity, almost comparable to penicillin for Staphylococcus aureus and Bacillus subtilis respectively. The derivatives 3g and 3l exhibited high antifungal activity. Moreover, antibacterial activities were more prolific than antifungal activity. The QSAR studies indicated the importance of topological parameters, Kiers second order molecular index (κα(2)) and molecular connectivity index (χ) in describing the antibacterial activity and electronic parameters, the energy of highest occupied molecular orbital (HOMO) and the dipole moment (µ) in describing the antifungal activity.