Biological evaluation of benzothiazoles obtained by microwave-green synthesis.

Benzothiazole compounds are known as an important bicyclic ring system with multiple applications. These compounds have a wide range of biological activities, including anticancer, antimicrobial, anti-inflammatory and antiviral activities. In this study, benzothiazole compounds were synthesized and their various biological activities were examined. The synthesized benzothiazoles were evaluated for their antimicrobial properties against various bacterial and fungal strains. The compound 6e is most active ligand in the series against bacteria and fungi as compared to standard antibiotics. Especially, this compound significant effect against Staphylococcus aureus (32.00 ± 1.73 mm). These compounds exhibited potent anticancer activity against gastrointestinal cancer cells, demonstrating their potential as therapeutic agents. The lowest antiproliferative response after administration of the compounds was observed in HCT116 cells, while the most effective antiproliferative response was observed in AGS cells (> 10 µg/mL). In all cell lines, 40 and 100 µg/mL application values of the selected compounds showed significant increases in the expression of caspase-3, 8 and 9. We also utilized a computational docking approach to investigate the interaction of these benzothiazoles with VEGFR-2 kinase. Our docking studies showed that compounds 6a and 6d may be promising therapeutic agents against gastrointestinal system cancers due to their ability to bind to VEGFR-2 kinase.

Synthesis, biological evaluation and mechanism of action of benzothiazole derivatives with aromatic hydrazone moiety, a new class of antileishmanial compounds.

Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC50 values of 28.86 and 7.70 µM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies.

Identification of Benzothiazoles Bearing 1,3,4-Thiadiazole as Antiproliferative Hybrids Targeting VEGFR-2 and BRAF Kinase: Design, Synthesis, BIO Evaluation and In Silico Study.

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds-4a, 4f, 4l, and 4r-demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77-66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.

Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 µM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

Review on Synthesis of 2-(2-Hydroxyaryl) Benzothiazoles (HBT) for Excited-State Intra-molecular Proton Transfer (ESIPT)-Based Detection of Ions and Biomolecules.

In this review, we present a systematic and comprehensive summary of the recent developments in the synthetic strategies of 2-(2-hydroxyarylsubstituted)-benzothiazole (HBT) framework along with incorporation of various substituents on phenolic and benzothiazole rings which affect the emission process. The literature, spanning the years 2015-2024, on excited-state intramolecular proton transfer (ESIPT)-based studies of HBT derivatives comprising the effects of solvent polarity, substituents, and extended conjugation on fluorophores has been searched. ESIPT, intramolecular charge transfer, and aggregation-induced emissions enable these fluorescent probes to specifically interact with analytes, thereby altering their luminescence characteristics to achieve analyte detection. These fluorescent probes exhibit large Stokes shifts, high quantum yields, and excellent color transitions. Finally, the applications of HBTs as ESIPT-based fluorescent probes for the detection of cations, anions, and biomolecules have been summarized. We anticipate that this review will provide a comprehensive overview of the current state of research in this field and encourage researchers to develop novel ESIPT-based fluorophores with new applications.

Synthesis, antibacterial and antibiofilm activity of new 1,2,3,5-tetrazine derivatives from coupling reactions of diazonium salt of 2-amino-6-nitrobenzothiazole with diverse substituted 2-aminobenzothiazole derivatives.

The coupling reaction of diazonium ion of 2-amino-6-nitrobenzothiazole at 0-5 °C with distinctly substituted 2-aminobenzothiazole derivatives produced new 1,2,3,5-tetrazine derivatives. It was found that diazotized 2-amino-6-nitrobenzo[d]thiazol reacts with the ring nitrogen atom of varyingly substituted 2-aminobenzothiazole derivatives to yield tetrazine nucleus. The benzene ring of benzothiazole bearing electron donor group and annelated to the tetrazine was further substituted in situ by other 6-nitrobenzo[d]thiazol-2-yl) diazinyl to yield the final product. The structure of the prepared compounds was elucidated using their physical, elemental, and spectroscopic data. The synthesized compounds were tested for their antimicrobial and antibiofilm activities against Staphylococcus aureus and Escherichia coli bacteria. Two of the synthesis tetrazine derivatives exhibited interesting antibiofilm potential.

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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Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.

Development of an 18F-labeled azobenzothiazole tracer for α-synuclein aggregates in the brain.

Nuclear imaging of aggregated α-synuclein pathology is an urgent clinical need for Parkinson's disease, yet promising tracers for brain α-synuclein aggregates are still rare. In this work, a class of compact benzothiazole derivatives was synthesized and evaluated for α-synuclein aggregates. Among them, azobenzothiazoles exhibited specific and selective detection of α-synuclein aggregates under physiological conditions. Fluoro-pegylated azobenzothiazole NN-F further demonstrated high-affinity binding to α-synuclein aggregates and efficient 18F-radiolabeling via nucleophilic displacement of a tosyl precursor. [18F]NN-F was stable in plasma in vitro and showed efficient brain uptake with little defluorination in vivo.

Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease.

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC50 < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC50 = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC inhibitor for the treatment of ADPKD.

In vitro inhibition of α-Synuclein aggregation and disaggregation of preformed fibers by polyphenol hybrids with 2-conjugated benzothiazole.

The misfolding and aggregation of α-Syn play a pivotal role in connecting diverse pathological pathways in Parkinson's disease (PD). Preserving α-Syn proteostasis and functionality by inhibiting its aggregation or disaggregating existing aggregates using suitable inhibitors represents a promising strategy for PD prevention and treatment. In this study, a series of benzothiazole-polyphenol hybrids was designed and synthesized. Three identified compounds exhibited notable inhibitory activities against α-Syn aggregation in vitro, with IC50 values in the low micromolar range. These inhibitors demonstrated sustained inhibitory effects throughout the entire aggregation process, stabilizing α-Syn proteostasis conformation. Moreover, the compounds effectively disintegrated preformed α-Syn oligomers and fibers, potentially by binding to specific domains within the fibers, inducing fibril instability, collapse, and ultimately resulting in smaller-sized aggregates and monomers. These findings offer valuable insights into the therapeutic potential of polyphenol hybrids with 2-conjugated benzothiazole targeting α-Syn aggregation in the treatment of PD.

Effective α-glycosidase inhibitors based on polyphenolic benzothiazole heterocycles.

α-Glycosidase inhibition is one of the main approaches to treat Diabetes mellitus. Polyphenolic moieties are known to be responsible for yielding exhibit potent α-glycosidase inhibitory effects. In addition, compounds containing benzothiazole and Schiff base functionalities were previously reported to show α-glycosidase inhibition. In this paper, the synthesis of seven new phloroglucinol-containing benzothiazole Schiff base derivatives through the reaction of 6-substituted-2-aminobenzothiazole compounds with 2,4,6-trihydroxybenzaldehyde using acetic acid as a catalyst was reported. The synthesized compounds were characterized using spectroscopic methods such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory effects on α-glycosidase, compounds 3f and 3g were found to show significant inhibitory properties when compared to the positive control. The IC50 values of 3f and 3g were calculated as 24.05 ± 2.28 and 18.51 ± 1.19 µM, respectively. Kinetic studies revealed that compounds 3f and 3g exhibited uncompetitive mode of inhibition against α-glycosidase. Molecular modeling predicted druglikeness for the title compounds and underpinned the importance of phloroglucinol hydroxyls for interacting with the key residues of α-glycosidase.

A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds.

To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H-benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the C2-arylacylation products in 70-95% yields for 38 examples. A plausible mechanism was also proposed based on a series of controlled experiments.

Synthesis and Antimicrobial, Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis.

In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a-e and pyrrolo[2,1-b][1,3]benzothiazoles 9a-e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (5a-e) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a-e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a-e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a,d, and 9a,d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a, d, and 9a,d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.

Discovery and structure-based design of a new series of potent and selective PPARδ agonists utilizing a virtual screening method.

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.

Novel benzothiazole-based dual VEGFR-2/EGFR inhibitors targeting breast and liver cancers: Synthesis, cytotoxic activity, QSAR and molecular docking studies.

A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10-12 and their ester analogues 21-23 displayed the highest anticancer activities with IC50 of 0.73-0.89 µM, against MCF-7 and IC50 of 2.54-2.80 µM, against HepG-2; compared to doxorubicin (IC50 = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21-23 showed a potent activity against the resistant MDA-MB-231 cell line with IC50 of 5.45-7.28 µM, relative to doxorubicin (IC50 = 7.46 µM) surpassing their carboxylic acid analogues 10-12 (IC50 of 8.88-11.02 µM). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15-0.19 µM) comparable to that of sorafenib (IC50 = 0.12 µM). Against EGFR, the ethyl ester derivatives 21-23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC50 of 0.11-0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors.

Synthesis and evaluation of novel 1-(((6-substitutedbenzo[d]thiazol-2-yl)amino)(heteroaryl)methyl)naphthalen-2-ol as pesticidal agents.

To discover new agrochemicals with prominent pesticidal properties, a series of novel ß-naphthol derivatives containing benzothiazolylamino and various heteroaryl groups (8a-q) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L-1) and diamondback moth (50-95% at 10 mg·L-1). Compounds 8 b, 8f, 8 g, 8j, 8k, 8n, and 8o possessed LC50 values of 0.0988-5.8864 mg·L-1 against diamondback moth. Compounds 8i, 8 l, and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L-1. Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h, 8i, and viii could activate the release of calcium ions in insect (M. separata) central neurons at a higher concentration (50 mg·L-1). The SAR analysis provided valuable information for further structural modifications.

Synthesis, anticancer evaluation and molecular docking of new benzothiazole scaffolds targeting FGFR-1.

This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2-12 and chain elongation with different amino acids and their corresponding ester derivatives 13-18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2-18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC50 HepG-2 = 2.06, 2.21 µM and IC50 MCF-7 = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC50 = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC50 = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G1 and G2/M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1-18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547.

Developing a scaffold for urease inhibition based on benzothiazoles: Synthesis, docking analysis, and therapeutic potential.

The synthesis, in silico molecular docking, and in vitro urease inhibition studies of a novel series of benzothiazole derivatives are reported. The title compounds in the two series, namely, 2-({5-[(benzothiazol-2-ylthio)methyl]-1,3,4-oxadiazol-2-yl}thio)-1-(4-substituted-phenyl)ethan-1-one and 2-(benzothiazol-2-ylthio)-1-(4-substituted-phenyl)ethan-1-one oxime, were synthesized by the reaction of benzo[d]thiazole-2-thiol with different kinds of intermediates in several steps using both conventional and microwave techniques. All compounds were found to have an excellent degree of urease-inhibitory potential ranging between 16.16 ± 0.54 and 105.32 ± 2.10 µM when compared with the standard inhibitor acetohydroxamic acid with IC50 = 320.70 ± 4.24 µM. The structure-activity relationship was established in detail. The binding interactions of the compounds with the enzyme were confirmed through molecular docking. Further, 100 -ns molecular dynamics simulations were performed to investigate the stability and structural perturbations experienced by the most potent compound over the urease active site.

Advances in 2-substituted benzothiazole scaffold-based chemotherapeutic agents.

Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential. Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents.