Synthesis, Characterization, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.

BACKGROUND: Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions. OBJECTIVES: Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as 1H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in µg/mL values. The antioxidant activity was also carried out using a DPPH assay. RESULTS: Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 µg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e). CONCLUSION: Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.

Extensive Multiple 2D-/3D-QSAR Modeling, Molecular Docking and Pharmacophoric Approaches for Piperazinylquinoline Derivatives as Respiratory Syncytial Virus Fusion Inhibitors.

BACKGROUND: The human respiratory syncytial virus (RSV) is responsible for causing upper and lower respiratory tract infections in young children. RSV Fusion (F) protein is a surface glycoprotein that facilitates virus entry into host cells. Thus, newer designing of RSV Fusion (F) protein inhibitors is required on an urgent basis. METHODS: In the present study, we have developed statistically robust. Quantitative structure-activity relationship (QSAR) models for the effective designing of newer analogues of piperazinylquinoline derivatives (H1-H12). RESULTS: Our developed models were retained with high statistical parameters (R2 > 0.6 and Q2 > 0.5). Our developed pharmacophore, model (AADHRR_2) (indicating that two hydrogen bond acceptors, one hydrogen bond donor, one hydrophobic group, and two aromatic rings) is crucial for retaining the activities of piperazinylquinoline derivatives against RSV. Moreover, docking analysis of 12 new analogues on RSV pre-F in complex with 5C4 Fab (PDB ID: 5W23) and post-F trimeric protein (PDB ID: 3RRR) suggested higher affinities of these molecules against studied targets with good docking scores. CONCLUSION: Thus, one can implement developed QSAR models, docking analogy and Pharmacophore models for identifications of potent leads for designed molecules as RSV Fusion (F) protein inhibitors.

A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.

This review presented the unique characteristics of different types of cyclodextrin polymers by non-covalent host-guest interactions to synthesize an inclusion complex. Various cancers are treated with different types of modified cyclodextrins, along with the anticancer drug paclitaxel. PTX acts as a mitotic inhibitor, but due to its low dissolution and permeability in aqueous solutions, it causes considerable challenges for drug delivery system (DDS) designs. To enhance the solubility, it is reformulated with derivatives of cyclodextrins using freeze-drying and co-solvent lyophilization methods. The present supramolecular assemblies involve cyclodextrin as a key mediator, which is encapsulated with paclitaxel and their controlled release at the targeted area is highlighted using different DDS. In addition, the application of cyclodextrins in cancer treatment, which reduces the off-target effects, is briefly demonstrated using various types of cancer cell lines. A new nano-formulation of PTX is used to improve the antitumor activity compared to normal PTX DDS in lungs and breast cancer is well defined in the present review.

Synthesis, Molecular docking, Antioxidant, Anti-TB, and Potent MCF-7 Anticancer Studies of Novel Aryl-carbohydrazide Analogues.

BACKGROUND: Hydrazide-hydrazone-based compounds are reported for their wider pharmacological potentials. METHODS: In the present work, we synthesized 10 new Schiff-based-aryl-carbohydrazide (3a-3e) and (4a-4e) analogues and characterized further using standard spectroscopic techniques including NMR, mass and FT-IR. Moreover, all synthesized compounds were subjected to in vitro anti-TB, anti-microbial, antioxidant and anti-MCF-7 cell line studies. RESULTS: Our results suggested that compounds have strong potencies against studied microbial species (such as 3a, 3b and 3c, (anti-TB activity: MIC value of 1.6 µg/mL; 3c:80.23 % inhibition at 200 µg/mL against MCF-7). Synthesized compounds (3a-3e) and (4a-4e) were also retained with higher docking scores than standards like ciprofloxacin; when studied for their molecular docking analysis against common anti-bacterial (pdb id:1d7u; 3a: -4.909 kcal/mol), common anti-fungal (pdb id:1ai9; 3b: -6.122 kcal/mol) and enoyl acyl reductase enzyme (pdb id:2x22; 3c: docking score: -4.194 kcal/mol)) targets. CONCLUSION: Thus, considering promising results for Schiff-based-aryl-carbohydrazides, these compounds may emerge as a new class for developing potent anti-microbial agents in the near future.

Synthesis, In silico and In vitro Analysis of Hydrazones as Potential Antituberculosis Agents.

Tuberculosis (TB) is a major cause of mortality and illness as reported by the W.H.O in 2019. The WHO report also mentioned the fact that about 10.0 million people fell ill with tuberculosis in the year 2018. Hydrazide-hydrazones having azomethine group (-NH-N=CH-) connected with carbonyl group is reported for the number of bioactivities like anti-inflammatory, anticonvulsant, anticancer, antiviral and antiprotozoal. OBJECTIVE: The objective of our current study is to design and synthesise more potent hydrazide- hydrazones, containing anti-tubercular agents. METHODS: In the current study, we synthesized 10 hydrazones (3a-3j) by stirring corresponding benzohydrazides (2) with substituted aldehydes (1a-j) in ethanol as a solvent and acetic acid as a catalyst at room temperature. All synthesized compounds were characterized by various spectroscopic techniques including elemental analysis, ultraviolet-visible spectroscopy, fluorescence, fourier- transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. Compounds (3a-3j) were tested for in vitro anti-TB activity using Microplate Alamar Blue Assay (MABA). RESULTS: All our synthesized compounds (3a-3j) were found to be potent against Mycobacteria tuberculosis (H37RV strain) with MIC (minimum inhibitory concentrations) values of 3.125-50 µg/mL. The hydrazide CO-NH protons in (3a-j) compounds are highly deshielded and showed broad singlet at 9.520-9.168 ppm. All the compounds were found to have more intense emission in the 416 - 429 nm regions and strong absorption in the regions of 316 - 327 nm. Synthesized compounds were also tested for in silico analysis using different software for their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) analysis. All the compounds were found to be in silico non-carcinogenic. CONCLUSION: It will be worth saying that our in silico and in vitro approaches used in the current study will become a guide for medicinal chemists to make structural modifications and synthesize more effective and potent hydrazone containing anti-tubercular agents.

Synthesis, admetSAR Predictions, DPPH Radical Scavenging Activity, and Potent Anti-mycobacterial Studies of Hydrazones of Substituted 4-(anilino methyl) benzohydrazides (Part 2).

BACKGROUND: For the past several decades, the presence of tuberculosis (TB) is being remarked as the most common infectious disease leading to mortality. OBJECTIVE: Hydrazone containing azometine group (-NHN=CH-) compounds have been reported for a broad range of bioactivities such as antiplatelet, analgesic, anti-inflammatory, anticonvulsant, antidepressant, antimalarial, vasodilator, antiviral, and antimicrobial, etc. Methods: For the synthesis of compounds (4a-4d) and (6a-6e), aromatic amines were treated with methyl terephthalaldehydate in methanol, giving Schiff's bases, followed by reductive amination and further treatment with hydrazine hydrate gave acid hydrazides (4a-4d). These acid hydrazides were then treated with different aromatic aldehydes to yield hydrazones (6a-6d). All the synthesized compounds were subjected to FT-IR, NMR, and UV spectroscopic characterization. RESULTS: Compounds (4a-4d) and (6a-6e) were found to have highly potent activity against Mycobacteria tuberculosis (Vaccine strain, H37 RV strains): ATCC No- 27294 (MIC:1.6-6.25 µg/mL) than standard anti-TB drugs. The compounds exhibited good radical scavenging potentials(0- 69.2%), as checked from DPPH protocol. All compounds also demonstrated good in-silico ADMET results. CONCLUSION: The current study revealed promising in vitro anti-tuberculosis and anti-oxidant profiles of hydrazide-hydrazone analogues.

Synthesis, Spectroscopic, In-vitro and Computational Analysis of Hydrazones as Potential Antituberculosis Agents: (Part-I).

BACKGROUND: Since the last few decades, the healthcare sector is facing the problem of the development of multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) infections all over the world. Regardless of the current healthcare progress for the treatment of mycobacterial infections, we are still unable to control addition of every year 9 million new cases of tuberculosis (TB). OBJECTIVE: We had an objective to synthesize some novel hydrazones, which were further subjected to characterization, Photoluminescence study, in vitro anti-mycobacterium testing and in silico ADMET predictions. METHODS: Some new hydrazone derivatives have been successfully prepared by the condensation reaction in the present study. All the compounds were characterized by using FTIR, NMR, UV, Fluorescence spectroscopic techniques. RESULTS: All our newly synthesized compounds showed strong electronic excitation at 292.6 - 319.0 nm and displayed more intense emissions in the 348 - 365 nm regions except compound 3i. The newly synthesized hydrazones 3a, 3b, 3f and 3g were found to be the most active compounds and showed MIC (Minimum inhibitory concentrations) values of 12.5 µg/mL. CONCLUSION: In the realm of development of more potent, effective, safer and less toxic antituberculosis agents; our current study would definitely help the medicinal chemists to develop potent analogues containing hydrazine motifs in them.

Synthesis, SAR, Molecular Docking and Anti-Microbial Study of Substituted N-bromoamido-2-aminobenzothiazoles.

BACKGROUND: Benzothiazoles are reported to have bioorganic and pharmaceutical chemistry applications. INTRODUCTION: A series of substituted N-bromoamido-2-aminobenzothiazoles was synthesized from substituted anilines via 2-aminobenzothiazoles and it was further evaluated for its antimicrobial activity. METHODS: All the newly synthesized compounds were characterized by FT-IR, NMR and mass spectra and purity profiles were studied by HPLC analysis. The antimicrobial testing (MIC determination) was newly performed with agar micro-broth dilution method for these analogs. RESULTS: Among the synthesized compound 3b showed the highest activity with MIC value of 3.12 µg/mL against Bacillus, E. coli, S. aureus and Klebsiella and 6.25 µg/mL against C. albicans. The ADME properties as calculated by using Qikprop were found within acceptable range. Derivatives shows a good-moderate binding affinity towards target Cytochrome P450 14 alpha-sterol demethylase (CYP51) (PDB ID: 1EA1). CONCLUSION: Our in-silico and in-vitro studies on a series of substituted aminobenzothiazoles may be helpful for further designing of more potent antimicrobials in future.

Synthesis, In silico and Biological Studies of Thiazolyl-2h-chromen-2-one Derivatives as Potent Antitubercular Agents.

BACKGROUND: A series of new six thiazolyl-2-amine-based Schiff base derivatives (4a-4f) were synthesized by a sequential multistep reaction starting with Salicylaldehyde. METHODS: All the Schiff base derivatives were screened in-vitro for their antibacterial activity against Mycobacterium tuberculosis (H37RV strain) ATCC No-27294. The synthesized compounds were characterized by FTIR, 1H-NMR, 13C-NMR and Mass spectrometry. RESULTS: Among the compounds tested, 4c and 4f derivatives exhibited potent antitubercular activity against M. tuberculosis at MIC 6.25 µg/mL. CONCLUSION: We extended our study to explore the inhibition mechanism by conducting molecular docking analysis by using Schrodinger's molecular modeling software. All the newly synthesized compounds were found to be in-silico AMES test non-toxic and non-carcinogens. The good Qikprop's Absorption, Distribution, Metabolism and Excretion (ADMET) would definitely help the researchers in order to make more potent Anti-TB agents.

Synthesis, SAR, In silico Appraisal and Anti-Microbial Study of Substituted 2-aminobenzothiazoles Derivatives.

BACKGROUND: Antimicrobial resistance is a major global health problem, which is being rapidly deteriorating the quality of human health. Series of substituted N-(benzo[d]thiazol-2-yl)-2- (4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl)acetamide (3a-j) were synthesized from substituted N-(benzo[d]thiazol-2-yl)-2-chloroacetamide/bromopropanamide (2a-j) and 6-fluoro-3- (piperidin-4-yl)benzo[d]isoxazole (2) and further evaluated for their docking properties and antimicrobial activity. METHODS: All the synthesized compounds were characterized by FT-IR, NMR and Mass spectral analysis. All compounds were allowed to dock against different antimicrobial targets having PDB ID: 1D7U and against common antifungal target having PDB ID: 1EA1. RESULTS: The compounds 3d and 3h showed good activity against Methicillin-resistant Staphylococcus aureus (MRSA, resistance Gram-positive bacteria). All synthesized compounds showed good to moderate activity against selected bacterial and fungal microbial strains. If we compared the actual in-vitro antimicrobial activity and in silico molecular docking study, we found that molecules 3i and 3h were more potent than the others. CONCLUSION: Our current study would definitely pave the new way of designing and synthesis of more potent 2-aminobenzothiazoles derivatives.

Synthesis and Anti-mycobacterium Study on Halo-substituted 2-aryl oxyacetohydrazones.

BACKGROUND: The treatment of multiple-drug-resistant tuberculosis (MDR-TB) with currently available marketed drugs remains a global health concern. The cases of resistant tuberculosis patients are increasing day by day. OBJECTIVE: The objective of this study is to highlight the need of developing shorter, simpler and tolerable drug regimens. METHODS: In the present study, we synthesized various halo-substituted 2-aryloxyacetohydrazones via a series of reactions from halo-substituted phenols. All the compounds were characterized by using various spectroscopic methods, such as NMR, FT-IR, UV spectroscopy, etc. Results: All the synthesized hydrazones showed theoretically good interactions with enzyme enoyl reductase (pdb id: 4tzk). All the synthesized compounds (5a-5o) showed moderate to good activity (3.125-100 µg/mL) against Mycobacteria tuberculosis, H37RV strain. CONCLUSION: Our results would pave a new way for the development of more effective Anti-TB agents in the future.

Synthesis and Biological Evaluation of New Hydrazone Derivatives of Quinoline and Their Cu(II) and Zn(II) Complexes against Mycobacterium tuberculosis.

A new series of quinoline hydrazone derivatives and their metal complexes have been synthesized and their biological properties have been evaluated against Mycobacterium tuberculosis (H37 RV strain). Most of the newly synthesized compounds displayed 100% inhibitory activity at a concentration of 6.25-25 µg/mL, against Mycobacterium tuberculosis. Fluorescence properties of all the synthesized compounds have been studied.

Novel Zinc(II) Complexes of Heterocyclic Ligands as Antimicrobial Agents: Synthesis, Characterisation, and Antimicrobial Studies.

The synthesis and antimicrobial activity of novel Zn(II) metal complexes derived from three novel heterocyclic Schiff base ligands 8-[(Z)-{[3-(N-methylamino)propyl]imino}methyl]-7-hydroxy-4-methyl-2H-chromen-2-one, 2-[(E)-{[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]imino}methyl]phenol, and (4S)-4-{4-[(E)-(2-hydroxybenzylidene)amino]benzyl}-1,3-oxazolidin-2-one have been described. These Schiff base ligands and metal complexes are characterised by spectroscopic techniques. According to these data, we propose an octahedral geometry to all the metal complexes. Antimicrobial activity of the Schiff base ligand and its metal complexes was studied against Gram negative bacteria: E. coli and Pseudomonas fluorescens, Gram positive bacteria: Staphylococcus aureus, and also against fungi, that is, C. albicans and A. niger. Some of the metal complexes show significant antifungal activity (MIC < 0.2 µ g/mL). The "in vitro" data has identified [Zn(NMAPIMHMC)2]·2H2O, [Zn(TMPIMP)2]·2H2O, and [Zn(HBABO)2]·2H2O as potential therapeutic antifungal agents against C. albicans and A. niger.