Medicinal bismuth: Bismuth-organic frameworks as pharmaceutically privileged compounds

Historically organometallic compounds have been used to cure certain diseases with limited applications. Although bismuth belongs to the category of heavy metals, many of its derivatives have found applications in modern drug discovery research, mainly because of its low toxicity and higher bioavailability. Being an eco-friendly mild Lewis acid, compounds having bismuth as a central atom are capable of binding several proteins in humans and other species. Bismuth complexes demonstrated antibacterial potential in syphilis, diarrhea, gastritis, and colitis. Apart from antibacterial activities, bismuth compounds exhibited anticancer, antileishmanial, and some extent of antifungal and other medicinal properties. This article discusses major synthetic methods and pharmacological potentials of bismuth complexes exhibiting in vitro activity to significant clinical performance in a systematic and timely manner.Copyright © 2022 Elsevier Ltd

Synthesis of new 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole derivatives as potential cytotoxic and antimicrobial agents

Globally cancer is the second leading cause of death;a drug that can cure cancer with the utmost negligible side effects is still a distant goal. Due to increasing antibiotic resistance, microbial infection remains a grave global health security threat. The ongoing coronavirus pandemic increased the risk of microbial and fungal infection. A new series of 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole (7a-t) have been synthesized. The structure of synthesized compounds was confirmed by the spectrometric analysis. The newly synthesized compounds were screened for cytotoxic activity against breast cell lines MCF-7 and MDA-MB-231. Against the MCF-7 cell line compounds 7f, 7 g and 7n showed excellent activity with GI50 0.6 muM to <100 nM concentration. Compound 7b showed good activity against MDA-MB-231 cell line with GI50 47 muM. The active derivatives 7b, 7e, 7f, 7 g and 7n were further evaluated for cytotoxicity against the epithelial cell line derived from the human embryonic kidney (HEK 293) and were found nontoxic. The thiazolyl-1,2,4-oxadiazole derivatives were also screened to evaluate theirs in vitro antimicrobial potential against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100) and Aspergillus niger (ATCC 504). Amongst the 7a-t derivatives, six compounds 7a, 7d, 7f, 7n, 7o, 7r showed good antifungal activity against C. albicans and eight compounds 7c, 7d, 7 g, 7h, 7i, 7k, 7l and 7o showed good activity against A. niger. The potential cytotoxic and antifungal activity suggested that the thiazolyl-1,2,4-oxadiazole derivatives could assist in the development of lead compounds for the treatment of cancer and microbial infections.Copyright © 2022 The Authors

Structure property relationship in two thiazole derivatives: Insights of crystal structure, Hirshfeld surface, DFT, QTAIM, NBO and molecular docking studies

Detailed structural and noncovalent interactions in two thiazole derivatives (N-(4-Bromophenyl)-2-(methylthio)thiazole-5-carboxamide and Ethyl-5-((4-bromophenyl)carbamoyl)thiazole-4-carboxylate) are investigated by single crystal X-ray diffraction study and computational approaches. The structure investigation revealed that various interactions like C-H…O, N-H…O, and N-H…N hydrogen bonds and Br…Br interactions are involved in constructing ring motifs to stabilize the crystal packing. Hirshfeld surface analysis and fingerprint plots were carried out to study the differences and similarities in the relative contribution of noncovalent interactions in both the molecules. The FMOs and other global reactive parameters are analyzed for thiazole derivatives. The strength and nature of weak interactions present in the molecule were characterized by RDG-based NCI and QTAIM analyses. Natural bond orbital (NBO) analysis unravels the importance of non-covalent and hyperconjugative interactions for the stability of the molecules in their solid state. Further, molecular docking of N-(4-Bromophenyl)-2-(methylthio)thiazole-5-carboxamide and Ethyl-5-((4-bromophenyl)carbamoyl)thiazole-4-carboxylate with SARS-Covid-19 have been carried out. © 2023 Taylor & Francis Group, LLC.

Synthesis, characterization, and theoretical investigation of 4-chloro-6(phenylamino)- 1,3,5-triazin-2-yl)asmino-4- (2,4-dichlorophenyl)thiazol-5-yl-diazenyl) phenyl as potential SARS-CoV-2 agent

The synthesis of 4-chloro-6(phenylamino)-1,3,5-triazin-2-yl)amino-4-(2,4 dichlorophenyl)thiazol-5-yl-diazenyl)phenyl is reported in this work with a detailed structural and molecular docking study on two SARS-COV-2 proteins: 3TNT and 6LU7. The studied compound has been synthesized by the condensation of cyanuric chloride with aniline and characterized with various spectroscopic techniques. The experimentally obtained spectroscopic data has been compared with theoretical calculated results achieved using high-level density functional theory (DFT) method. Stability, nature of bonding, and reactivity of the studied compound was evaluated at DFT/ B3LYP/6-31 + (d) level of theory. Hyper-conjugative interaction persisting within the molecules which accounts for the bio-activity of the compound was evaluated from natural bond orbital (NBO) analysis. Adsorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of the experimentally synthesized compound was studied to evaluate the pharmacological as well as in silico molecular docking against SARS-CoV-2 receptors. The molecular docking result revealed that the investigated compound exhibited binding affinity of -9.3 and -8.8 for protein 3TNT and 6LU7 respectively. In conclusion, protein 3TNT with the best binding affinity for the ligand is the most suitable for treatment of SARS-CoV-2. © 2022 Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.

SARS-CoV-2 Mpro binding profile and drug-likeness of two novel thiazole derivatives: structural elucidation, DFT studies, ADME-T and molecular docking simulations.

Two novel thiazole derivatives, ethyl 5-((4-fluorophenyl)carbamoyl)-thiazole-4-carboxylate (2b) and ethyl 5-(p-tolylcarbamoyl)thiazole-4-carboxylate (6b) have been synthesized, and their crystal structures determined by X-ray diffraction. To rationalize their structure, reactivity and druggability, we have performed a series of separate, but complementary studies. Hirshfeld surface and 2D-fingerprint plots were first scrutinized to qualitatively unveil all the intermolecular interactions that ensure their crystal packing. Moreover, topological electron density parameters established from the quantum theory of atoms-in-molecules (QTAIM) and Reduced Density Gradient (RDG) were later relied on to characterize the chemical bonding of these species, in terms of the nature and magnitude of noncovalent interactions developed within their monomeric and dimeric forms. In both structures, C-H…O hydrogen bonds are found to be stronger than other noncovalent interactions. Furthermore, H…H bonding contacts and non-conventional C-H…O hydrogen bonds both exhibit a closed shell nature, and play in crucial role in the stability of the novel thiazoles. The isosurfaces in the intermolecular region furnished by NCI molecular diagram signifies the existence of weak noncovalent interactions. Finally, the potential inhibitory activity of the titled compounds and their drug-likeness are demonstrated by molecular docking and ADME-T calculations respectively. Both compounds adhere to the Lipinski's rule of five and present encouraging pharmacokinetic properties and safety profiles.Communicated by Ramaswamy H. Sarma.

Synthesis of new 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole derivatives as potential cytotoxic and antimicrobial agents

Globally cancer is the second leading cause of death;a drug that can cure cancer with the utmost negligible side effects is still a distant goal. Due to increasing antibiotic resistance, microbial infection remains a grave global health security threat. The ongoing coronavirus pandemic increased the risk of microbial and fungal infection. A new series of 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole (7a-t) have been synthesized. The structure of synthesized compounds was confirmed by the spectrometric analysis. The newly synthesized compounds were screened for cytotoxic activity against breast cell lines MCF-7 and MDA-MB-231. Against the MCF-7 cell line compounds 7f, 7g and 7n showed excellent activity with GI50 0.6 μM to <100 nM concentration. Compound 7b showed good activity against MDA-MB-231 cell line with GI50 47 μM. The active derivatives 7b, 7e, 7f, 7g and 7n were further evaluated for cytotoxicity against the epithelial cell line derived from the human embryonic kidney (HEK 293) and were found nontoxic. The thiazolyl-1,2,4-oxadiazole derivatives were also screened to evaluate theirs in vitro antimicrobial potential against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100) and Aspergillus niger (ATCC 504). Amongst the 7a-t derivatives, six compounds 7a, 7d, 7f, 7n, 7o, 7r showed good antifungal activity against C. albicans and eight compounds 7c, 7d, 7g, 7h, 7i, 7k, 7l and 7o showed good activity against A. niger. The potential cytotoxic and antifungal activity suggested that the thiazolyl-1,2,4-oxadiazole derivatives could assist in the development of lead compounds for the treatment of cancer and microbial infections.

Structural and Functional Insights of Thiazole Derivatives as Potential Anti-inflammatory Candidate: A New Contender on Chronic and Acute SARS-CoV-2 Inflammation and Inhibition of SARS-CoV-2 Proteins

Thiazoles are notable five-membered heterocyclic rings and their moieties can be found in several biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. Inflammation is the common cause that is associated with different disorders and diseases such as psoriasis, arthritis, infections, asthma, cancer, etc. In this article, the synthesis pattern of these novel molecules are discussed and their anti-inflammatory activities against cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) were reviewed and documented. The potent 26 thiazole analogs were validated with molecular docking against main protease (6LU7) and spike binding domain ACE2 receptor (6M0J) to defeat from the COVID-19 infections. Among this, THI9a showed excellent binding energy and affinity against deadly SAR CoV-2. The reviewed and theoretical study information strongly suggested that thiazole derivatives can be used for the development of futuristic target drugs against death-causing diseases like SAR-CoV-2. © 2022 Chemical Publishing Co.. All rights reserved.

Synthesis of Novel Aminothiazole Derivatives as Promising Antiviral, Antioxidant and Antibacterial Candidates.

It is well-known that thiazole derivatives are usually found in lead structures, which demonstrate a wide range of pharmacological effects. The aim of this research was to explore the antiviral, antioxidant, and antibacterial activities of novel, substituted thiazole compounds and to find potential agents that could have biological activities in one single biomolecule. A series of novel aminothiazoles were synthesized, and their biological activity was characterized. The obtained results were compared with those of the standard antiviral, antioxidant, antibacterial and anticancer agents. The compound bearing 4-cianophenyl substituent in the thiazole ring demonstrated the highest cytotoxic properties by decreasing the A549 viability to 87.2%. The compound bearing 4-trifluoromethylphenyl substituent in the thiazole ring showed significant antiviral activity against the PR8 influenza A strain, which was comparable to the oseltamivir and amantadine. Novel compounds with 4-chlorophenyl, 4-trifluoromethylphenyl, phenyl, 4-fluorophenyl, and 4-cianophenyl substituents in the thiazole ring demonstrated antioxidant activity by DPPH, reducing power, FRAP methods, and antibacterial activity against Escherichia coli and Bacillus subtilis bacteria. These data demonstrate that substituted aminothiazole derivatives are promising scaffolds for further optimization and development of new compounds with potential influenza A-targeted antiviral activity. Study results could demonstrate that structure optimization of novel aminothiazole compounds may be useful in the prevention of reactive oxygen species and developing new specifically targeted antioxidant and antibacterial agents.

Synthesis, characterization, and theoretical investigation of 4-chloro-6(phenylamino)-1,3,5-triazin-2-yl)asmino-4-(2,4-dichlorophenyl) thiazol-5-yl-diazenyl)phenyl as potential SARS-CoV-2 agent

The synthesis of 4-chloro-6(phenylamino)-1,3,5-triazin-2-yl)amino-4-(2,4 dichlorophenyl)thiazol-5-yl-diazenyl)phenyl is reported in this work with a detailed structural and molecular docking study on two SARS-COV-2 proteins: 3TNT and 6LU7. The studied compound has been synthesized by the condensation of cyanuric chloride with aniline and characterized with various spectroscopic techniques. The experimentally obtained spectroscopic data has been compared with theoretical calculated results achieved using high-level density functional theory (DFT) method. Stability, nature of bonding, and reactivity of the studied compound was evaluated at DFT/B3LYP/6-31 + (d) level of theory. Hyper-conjugative interaction persisting within the molecules which accounts for the bio-activity of the compound was evaluated from natural bond orbital (NBO) analysis. Adsorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of the experimentally synthesized compound was studied to evaluate the pharmacological as well as in silico molecular docking against SARS-CoV-2 receptors. The molecular docking result revealed that the investigated compound exhibited binding affinity of -9.3 and -8.8 for protein 3TNT and 6LU7 respectively. In conclusion, protein 3TNT with the best binding affinity for the ligand is the most suitable for treatment of SARS-CoV-2.

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications.

Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Structurally, there are two types of five-membered triazoles: 1,2,3-triazole and 1,2,4-triazole. Due to the structural characteristics, both 1,2,3- and 1,2,4-triazoles are able to accommodate a broad range of substituents (electrophiles and nucleophiles) around the core structures and pave the way for the construction of diverse novel bioactive molecules. Both the triazoles and their derivatives have significant biological properties including antimicrobial, antiviral, antitubercular, anticancer, anticonvulsant, analgesic, antioxidant, anti-inflammatory, and antidepressant activities. These are also important in organocatalysis, agrochemicals, and materials science. Thus, they have a broad range of therapeutic applications with ever-widening future scope across scientific disciplines. However, adverse events such as hepatotoxicity and hormonal problems lead to a careful revision of the azole family to obtain higher efficacy with minimum side effects. This review focuses on the structural features, synthesis, and notable therapeutic applications of triazoles and related compounds.

Thiazole-based SARS-CoV-2 protease (COV Mpro ) inhibitors: Design, synthesis, enzyme inhibition, and molecular modeling simulations.

As an attempt to contribute to the efforts of combating the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19, new analogs of the repurposed drug nitazoxanide which showed promising inhibitory efficacy on a viral protease enzyme were designed, synthesized and evaluated for their inhibitory activity on the main protease of the SARS-CoV-2 virus, using the COV2-3CL protease inhibition assay. The obtained results showed that the N-(substituted-thiazol-2-yl)cinnamamide analogs 19, 20, and 21 were the most active compounds with IC50 values of 22.61, 14.7, 21.99 µM, respectively, against the viral protease compared to the reference drugs, nitazoxanide, and lopinavir. Molecular modeling studies showed binding interactions of 19, 20, and 21 with hydrogen bonds to Gln189 and Glu166, arene-arene interaction between the thiazole moiety and His41, and other hydrophobic interactions between the ethene spacer moiety and Asn142. Moreover, an extra arene-arene interaction between substituted benzo[d]thiazole and His41 was observed regarding compounds 19 and 21. Surface mapping and flexible alignment proved the structural similarity between the new drug candidates and nitazoxanide. Compliance of the new compounds to Lipinski's rule of five was investigated and absorption, distribution, metabolism, excretion, and toxicology data were predicted. The newly synthesized compounds are promising template ligands for further development and optimization.

Heterocyclic compounds derived from cyclohexane-1,4-dione: synthesis of tetrahydro-4H-chromene and tetrahydrobenzo[d]thiazole derivatives as target SARS-CoV-2 main protease (Mpro) and potential anti-Covid-19

Tetrahydro-4H-chromene-3-carbonitrile derivatives 4a-c where prepared from the reaction of 1,4-cyclohexane dione (1), malononitrile (2) and either of benzaldehyde (3a), 2-chlorobenzaldehyde (3b) or 4-methoxybenzaldehyde (3c) in ethanol containing triethylamine. Compound 4b was used to prepare pyrazole, pyrimidine and thiazole derivatives. Moreover, tetrahydrobenzo[d]thiazole derivative 18 was prepared from the reaction of 1,4-cyclohexane dione (1) with elemental sulfur followed by phenyl isothiocyanate (12) in absolute ethanol containing triethylamine. The latter compound reacted with ethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce the 9-ethoxy-2H-chromeno[6,5-d]thiazole derivatives 20a,b. In addition, fused thiophene and pyran derivatives were synthesized starting from compound 18. The screened compounds were designed as mimics of the transition state of RNA2’-O-methylation were screened against several viral RNA 2’-OMTases from SARS-CoV (nsp10/nsp16 complex), Zika, West Nile, dengue, vaccinia (VP39) viruses. At the same time, the compounds were tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and vaccinia D1-D12 complex to evaluate their specificity. Compounds 4a, 4b, 6b, 6c, 6e, 9a, 9b, 15, 16, 21b, and 23b showed high % inhibitions against SARs-Cov nsp 14 with values 93.42, 87.49, 98.23, 88.15, 89.24, 96.31, 93.28, 89.25, 89.20, 87.24, and 94.49, respectively.

Synthesis of New Binary Thiazole-Based Heterocycles and Their Molecular Docking Study as COVID-19 Main Protease (Mpro) Inhibitors.

Isolated polynuclear binary heterocyclic compounds containing thiazole building block combined with benzofuran, pyrrole, thiazole, or thiophene via carboxamide and/or secondary amine as a junction are presented. The synthetic strategy of those is based on utilization of 2-chloroacetamido-4-phenylthiazole in the synthesis of binary heterocyclic compounds by cyclocondensation with salicylic aldehyde, acetonitrile derivatives, ammonium thiocyanate, 3-mercaptoacrylonitrile derivatives, and/or 3-mercaptoacrylate derivatives. The prepared binary thiazole-based heterocycles have been studied as protease (Mpro) inhibitors by molecular docking for visualization of their orientation and interactions with COVID-19 units using hydroxychloroquine as a reference molecule.

Synthesis, antioxidant, antimicrobial and antiviral docking studies of ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates.

A series of ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates (2a-r) was synthesized in two steps from thiosemicarbazones (1a-r), which were cyclized with ethyl bromopyruvate to ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates (2a-r). The structures of compounds (2a-r) were established by FT-IR, 1H- and 13C-NMR. The structure of compound 2a was confirmed by HRMS. The compounds (2a-r) were then evaluated for their antimicrobial and antioxidant assays. The antioxidant studies revealed, ethyl 2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazole-4-carboxylate (2g) and ethyl 2-(2-(1-phenylethylidene)hydrazinyl)thiazole-4-carboxylate (2h) as promising antioxidant agents with %FRSA: 84.46 ± 0.13 and 74.50 ± 0.37, TAC: 269.08 ± 0.92 and 269.11 ± 0.61 and TRP: 272.34 ± 0.87 and 231.11 ± 0.67 µg AAE/mg dry weight of compound. Beside bioactivities, density functional theory (DFT) methods were used to study the electronic structure and properties of synthesized compounds (2a-m). The potential of synthesized compounds for possible antiviral targets is also predicted through molecular docking methods. The compounds 2e and 2h showed good binding affinities and inhibition constants to be considered as therapeutic target for Mpro protein of SARS-CoV-2 (COVID-19). The present in-depth analysis of synthesized compounds will put them under the spot light for practical applications as antioxidants and the modification in structural motif may open the way for COVID-19 drug.

Triazole, imidazole, and thiazole-based compounds as potential agents against coronavirus.

The expansion of the novel coronavirus known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), COVID-19 (coronavirus disease 2019), or 2019-nCoV (2019 novel coronavirus) is a global concern over its pandemic potential. The need for therapeutic alternatives to stop this new pandemic is urgent. Nowadays, no efficacious therapy is available, and vaccines and drugs are underdeveloped to cure or prevent SARS-CoV-2 infections in many countries. Some vaccines candidates have been approved; however, a number of people are still skeptical of this coronavirus vaccines. Probably because of issues related to the quantity of the vaccine and a possible long-term side effects which are still being studied. The previous pandemics of infections caused by coronavirus, such as SARS-CoV in 2003, the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, HCoV-229E, and HCoV-OC43 were described in the 1960 s, -HCoV-NL63 isolated in 2004, and HCoV-HKU1identified in 2005 prompted researchers to characterize many compounds against these viruses. Most of them could be potentially active against the currently emerging novel coronavirus. Five membered nitrogen heterocycles with a triazole, imidazole, and thiazole moiety are often found in many bioactive molecules such as coronavirus inhibitors. This present work summarizes to review the biological and structural studies of these compound types as coronavirus inhibitors.