Tuberculosis Enoyl-acyl Carrier Protein Research Articles

Synthesis, physicochemical characterisation of novel Azo-2-{[(E)-{2-hydroxy-3-methoxy-5-[(E)-(4-nitrophenyl)diazenyl]phenyl}methylidene]amino}pyridin-3-ol and its metal complexes; evaluation of anti-diabetic, anti-tuberculosis, DFT, Docking and Electrochemical detection of pain relief Paracetamol

A azo-dye Schiff base 2-{[(E)-{2-hydroxy-3-methoxy-5-[(E)-(4-nitrophenyl)diazenyl]phenyl}methylidene]amino}pyridin-3-ol (HMNP) and its metal complexes. viz., [M(HMNP)2], [M= Co2+, Ni2+ and Cu2+] were synthesised and characterised by physicochemical techniques. All data suggest that the HMNP is tridentate ligand and its metal complexes have octahedral geometry. The optimized chemical parameters evaluated using DFT studies. Molecular docking has been performed by mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA) receptor to predict the binding affinity. The [Cu(HMNP)2] exhibited binding energy of -292.12 kcal/mol. In vitro antidiabitic and anti-tuberculosis activity showed that the complexes exhibited promising growth inhibition with effective IC50 potency values. Recent diagnoses about diabetes, tubercular and covid-19 patients have shown respiratory tract and inflammatory infections. In such patients paracetamol improve the resistance against infections. In this connection, electrochemical detection of paracetamol by a glassy carbon electrode modified using [Co(HMNP)2]. The analytical profile of [Co(HMNP)2]/GCE showed that the LOD of paracetamol (0.166 and 0.133 µM/L) linear range are (0.5-8 and 0.4-45 µM/L) and sensitivity is (0.451 and 6.452 μAμM−1cm-2) which were investigated by both CV and DPV technique's. Further, the prepared sensor, [Co(HMNP)2]/GCE has more stability and showed less leaching property.

Identification of antimycobacterial 8-hydroxyquinoline derivatives as in vitro enzymatic inhibitors of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase

The increasing prevalence of drug-resistant Mycobacterium tuberculosis strains stimulates the discovery of new drug candidates. Among them are 8-hydroxyquinoline (8HQ) derivatives that exhibited antimicrobial properties. Unfortunately, there is a lack of data assessing possible targets for this class mainly against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (MtInhA), a validated target in this field. Thus, the main purpose of this study was to identify 8HQ derivatives that are active against M. tuberculosis and MtInhA. Initially, the screening against the microorganism of a small antimicrobial library and its new derivatives that possess some structural similarity with MtInhA inhibitors identified four 7-substituted-8HQ (series 5 – 5a, 5c, 5d and 5i) and four 5-substituted-8HQ active derivatives (series 7 – 7a, 7c, 7d and 7j). In general, the 7-substituted 8-HQs were more potent and, in the enzymatic assay, were able to inhibit MtInhA at low micromolar range. However, the 5-substituted-8-HQs that presented antimycobacterial activity were not able to inhibit MtInhA. These findings indicate the non-promiscuous nature of 8-HQ derivatives and emphasize the significance of selecting appropriate substituents to achieve in vitro enzyme inhibition. Finally, 7-substituted-8HQ series are promising new derivatives for structure-based drug design and further development.

Evaluation of novel pyridoxal isonicotinoyl hydrazone (PIH) derivatives as potential anti‐tuberculosis agents: An in silico investigation

AbstractThis investigation employed computational methodologies to assess the therapeutic potential of derivatives (1–16) of pyridoxal isonicotinoyl hydrazone (PIH) as potential treatments for tuberculosis. Various computational techniques, including molecular dynamics simulation, molecular docking, density functional theory, and global chemical descriptors, were employed to analyze the interactions between the ligands and target proteins. Docking results indicated that ligands 6, 7, 8, and rifampin exhibited binding affinities of −8.4, −7.4, −9.2, and − 7.2 kcal mol−1, respectively, against mycobacterium tuberculosis enoyl acyl carrier protein reductase (INHA), with ligand 8 demonstrating superior inhibition. Molecular dynamics (MD) simulations were utilized to assess the stability of protein‐ligand interactions. Remarkably, the Root Mean Square Deviation (RMSD) of the INHA‐ligand 8 complex remained minimal, with peak values at .40, .56, .37, and .50 nm at temperatures of 300, 305, 310, and 320 K, respectively. This suggests superior stability compared to the reference drug rifampin and INHA complex, which exhibited an RMSD range of .2 to .8 nm at 300 K. Furthermore, analysis using Frontier Molecular Orbital (FMO) revealed that the Egap value of ligand 8 (4.407 eV) is lower than all the reference drugs except rifampin. This comprehensive theoretical analysis positions ligand 8 as a promising candidate for anti‐tuberculosis drug development, underscoring the need for further exploration through in vitro and in vivo studies.

Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA)

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

Isatin-pyrimidine hybrid derivatives as enoyl acyl carrier protein reductase (InhA) inhibitors against Mycobacterium tuberculosis

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and 3.9 µg/mL, respectively). Molecular docking studies suggest that this compound binds through the use of relatively unexplored hydrophobic pocket in the active site. Molecular dynamics was used to investigate and support the stability of 4l complex with the target enzyme. This study paves the way for the design and synthesis of novel antitubercular drugs.

Antitüberküloz Triptantrin analoglarının elektronik ve topolojik özelliklerinin ve enoil-ACP redüktaz ile etkileşimlerinin in silico yöntemlerle incelenmesi

Objective:
 This study aimed to investigate the structure-antitubercular activity relationships of a series of tryptanthrin analogues and the binding mechanisms of these analogues with InhA, Mycobacterium tuberculosis enoyl-acyl carrier protein (enoyl-ACP) reductase.
 Methods:
 Structure-activity relationships were investigated by using Electronic-Topological Method combined with Neural Networks (ETM-NN). Binding energies and non-covalent interactions stabilizing the ligand-InhA complex were obtained from the results of molecular docking. To assess these interactions, frontier molecular orbital analysis of the ligand-InhA complexes were also analysed. 
 Results: 
 The results of the ETM-NN application to the series of compounds in view are pharmacophoric and anti-pharmacophoric molecular fragments, which are characteristic of the class of compounds demonstrating activity against Mycobacterium tuberculosis strain H37Rv. The statistical characteristics of five pharmacophores (Phi) and five anti-pharmacophores (APhi) entering the forecasting system, are 0.90 and 0.86, correspondingly. Analysis of the electron density distribution has shown that the more effective binding with receptor was observed for active compounds.
 Conclusions: 
 A system of prognosis for the anti-tubercular activity of Mycobacterium tuberculosis H37Rv was developed on the base of the pharmacophores found, docking results, and electronic structure calculations. This prognosis system allows for designing of new potent antitubercular drugs.
 Keywords: Tryptanthrin analogues, mycobacterium tuberculosis H37Rv, InhA electronic-topological method, molecular docking, density functional theory

Discovery of potent triterpenoid and limonoid compounds targeting Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA): An in silico investigation

Drug resistance remains one of the primary concerns in treating tuberculosis (TB), making it imperative to find new and effective drug candidates for improved TB treatment. Enoyl acyl carrier protein reductase (InhA), an enzyme involved in mycolic acid biosynthesis, is crucial for anti-TB drug activity such as isoniazid (INH). Triterpenoids and limonoids are widespread in the plant kingdom and have gained much attention in their development as anti-TB agents. This study aims to examine the potential of triterpenoid and limonoid compounds as InhA inhibitors based on binding energy, interaction mode, and binding stability using docking and molecular dynamics (MD) investigation. Chisopatens A (−10.93 kcal/mol), 3-epi-cabraleahydroxy lactone (−9.85 kcal/mol), and 3-oxo-olean-11(12)en-28-oic acid (−9.73 kcal/mol), as well as 6α-(acetoxy)-14β,15β-epoxyazadirone (−9.77 kcal/mol), an azadirone-type limonoid derivative, have the best affinity for Leu63, Gly96, and Lys165 amino acid residues from InhA compared to native ligand (NAD) analyzed by docking studies. Chisopatens A, 3-epi-cabraleahydroxy lactone, and 3-oxo-olean-11(12)en-28-oic also had the best affinity for InhA based on MM-PBSA analysis, with values of −140.676 kJ/mol, −108.888 kJ/mol, and −162.605 kJ/mol, respectively. During dynamics studies, these compounds also showed good stability, protein compactness, and high-intensity interaction with InhA. These results strongly support future in-vitro studies to evaluate the efficacy of the hit compounds for treating INH-resistant MTB strains.

Novel 4-aminoquinolines: Synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase, antitubercular activity, SAR, and preclinical evaluation

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (MtInhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of MtInhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments.

Novel Hybrid 1,2,4- and 1,2,3-Triazoles Targeting Mycobacterium Tuberculosis Enoyl Acyl Carrier Protein Reductase (InhA): Design, Synthesis, and Molecular Docking.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis’ enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors 5b, 5c, 7c, 7d, 7e, and 7f successfully and totally (100%) inhibited the InhA enzyme. The IC50 values were calculated using different concentrations. With IC50 values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme’s binding site.

Design, synthesis and anti-Mycobacterium tuberculosis evaluation of new thiazolidin-4-one and thiazolo[3,2-a][1,3,5]triazine derivatives

In response to the urgent need to encounter infection diseases, and upon increasing concerns about the devastating effects of tuberculosis (TB), the promising thiazolidin-4-one scaffold was used as a starting point to design and synthesize seventeen new compounds, relying on the pharmacophoric features of different anti-Mycobacterium tuberculosis and antibacterial active compounds. Thiazolidin-4-one was elaborated to result in bi-functioning formation, and further ring fusion into a thiazolo[3,2-a][1,3,5]triazine, which was hybridized with different heterocyclic rings and sulfonamide moieties. All the newly synthesized compounds were evaluated for their activity against drug sensitive (DS), multi-drug resistant (MDR) and extensive drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains. Additionally, their anti-bacterial activity against several bronchitis causing-bacteria (ATCC) and their antifungal activity were assessed. Several compounds showed promising results regarding all of the mentioned assays without any antifungal activities. Particularly, compound 3 showed a promising activity against the three Mtb strains (DS, MDR and XDR) with MIC of 2.49, 9.91 and 39.72 µM, respectively. Furthermore, compound 7c revealed antituberculosis activity with MIC of 2.28, 18.14 and 36.31 µM against DS, MDR and XDR strains, respectively. Both of compounds 3 and 7c surpassed azithromycin on several bronchitis causing-bacteria and showed enhanced inhibitory activity against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA), with IC50 of 3.90 and 2.47 µM, respectively. The enzymatic activity was augmented by the binding characteristics of 3 and 7c in the InhA active site. Further investigations confirmed their safety on normal cell lines, and promising predicted ADME characteristics.

Synthesis, anti-TB activities, and molecular docking studies of 4-(1,2,3-triazoyl)arylmethanone derivatives.

Infectious diseases such as tuberculosis (TB) are leading causes of human death. Antibiotics are effective molecules to combat bacterial infections by affecting the processes required for bacterial cell growth and proliferation. The development of new antibiotics has become an important issue as overdosed or incorrect use of antibiotic lead to the development of antibiotic resistance. In this study, a new series of 4-(1,2,3-triazoyl)arylmethanone derivatives has been synthesized using the one-pot Copper-​Catalyzed Oxidative Cross-​Dehydrogenative Coupling​/Oxidative Cycloaddition strategy to overcome the aforementioned problems. New compounds were characterized by using spectroscopic techniques (1 H, 13 C-APT-NMR, FT-IR, and HRMS-TOF). In vitro antimycobacterial activities of the arylmethanone derivatives against the Mycobacterium tuberculosis H37 Rv standard strain were examined using the resazurin microplate method in the presence of streptomycin and rifampycin as standard medicines. Bioactive assays demonstrated promising results that some of the synthesized 4-(1,2,3-triazoyl)arylmethanone derivatives exhibited good anti-TB activities. Notably, compounds 6b, 6f, and 6g gave the most potent efficiency with minimum inhibitory concentration values of 4 μg/ml (12.8, 11.7, and 12.8 μΜ, respectively). Among the synthesized compounds, the cytotoxicity measurements of the 6b, 6f, 6g, 6d, and 6v derivatives were screened and it was found that the 6f derivative did not show any cytotoxicity. Molecular docking analyses are utilized to identify the binding mode and the key interactions between target compounds and the ligand-binding site of M. tuberculosis enoyl-acyl carrier protein reductase enzyme (MtInhA, EC 1.3.1.9). The docking results were in agreement with the in vitro results, which confirm the synthesized ligands bind to MtInha with moderate to low affinity.

Design, Synthesis and Biological Investigation of Some Novel Quinazolin-4(3H)-One Tethered 1, 3, 4-Thiadiazole-Thiol Motifs as Direct Enoyl Acyl Carrier Protein Reductase Inhibitors

Aims: In this study was two noteworthy pharmacophores quinazolin-4(3H)-one and 1,3,4-thiadiazole through methylene bridge were utilized to design, synthesize and characterize some novel 2-methyl quinazolin-4(3H)-one and 6-chloro-2-methyl quinazolin-4(3H)-one tethered S-substituted-1,3,4-thiadiazole-thiol structural analogs respectively as direct Mycobacterium Tuberculosis (MTB) enoyl acyl carrier protein reductase (InhA) inhibitors.
 Study Design: Design of structural analogs of quinazolin-4(3H)-one tethered 1,3,4-thiadiazole-thiol through methylene bridge by functional group modifications in core scaffold followed by computational studies to select promising compounds. Synthesis of some novel compounds, structural characterization and screening of biological activity of the same.
 Methodology: The molecular docking of designed compunds was carried out using schrodinger Glide XP into the active site of MTB InhA with protein data bank code (PDB ID: 2H7M). The interactions were evaluated based on the glide G score compared with reference standard isoniazid. Ten new compounds 7(A1-A10) were synthesized, characterized and screened for their in-vitro antitubercular activity by Microplate Almar Blue Assay (MABA) method followed by cytotoxicity evaluation of compounds 7A4 and 7A10 using Vero cell line.
 Results: All the designed compounds of series 7(A1-A10) had drug-like characteristics and were non-toxic to normal cells. In the molecular docking studies, compounds 7A4, 7A5, and 7A10 demonstrated strong binding affinity in the active region of MTB InhA protein and retained necessary amino acid interaction, similar to co-crystal 2H7M. Synthesized compounds 7(A1-A10) were found to have good antitubercular activity. Out of the series the compounds 7A4 and 7A10 were found to possess excellent antitubercular activity equipotent to reference standard streptomycin with minimum inhibitory concentration (MIC) value of 6.25µg/ml. The cytotoxic potential of compounds 7A4 and 7A10 showed remarkable selectivity index against Vero cell line.
 Conclusion: The findings of this study highlights the importance of tethering two pharmacophoric motifs in one compound to develop novel antitubercular agents that can be exploited as promising leads as direct InhA inhibitors.

Antitubercular and antibacterial activities of isoxazolines derived from natural products: Isoxazolines as inhibitors of Mycobacterium tuberculosis InhA

Isoxazoline derivatives of the natural products eugenol, 1’- S-acetoxychavicol acetate and sclareol are prepared through 1,3-dipolar cycloaddition reactions in an aqueous buffered system. The compounds are evaluated for their antitubercular and antibacterial activities. Compounds 2, 2a and 3f display strong antitubercular activity with minimum inhibitory concentration values of 26.68, 17.89 and 14.58 µM, respectively. Furthermore, derivative 3f exhibits antibacterial activity against Bacillus cereus (minimum inhibitory concentration value of 29.16 µM). Isoxazoline derivatives of 1’- S-acetoxychavicol acetate demonstrate improvements in cytotoxicity, and derivative 3f of sclareol demonstrates improved antitubercular and antibacterial activities. Isoxazolines derived from natural products exhibit Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) inhibitory activity, and molecular modelling predicts that they form hydrogen bonding and hydrophobic interactions with NADH and with the key residues of the InhA binding site.

Docking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate

In this research, we have designed four isoniazid derivatives, i.e., isonicotinohydrazide (1-isonicotinoyl semicarbazide, 1-thiosemi isonicotinoyl carbazide, N '-(1, 3-dimethyl-1 h-pyrazole-5-carbonyl) isonicotino hydrazide, and N '-(1,2,3- 4-thiadiazole-carbonyl) isonicotinohydrazide. The docking and molecular dynamic have performed to them to study its interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA). Based on this research, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA) receptor so that they could be used as an anti-tuberculosis drug candidate

Targeting Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase Using Computational Tools for Identification of Potential Inhibitor and their Biological Activity.

Enoyl-acyl carrier protein reductase (InhA) of type II fatty acid synthase system is involved in the synthesis of mycolic acids which is a major component of the bacterial cell wall. Since they are the key enzymes playing a very significant role in the FASII pathway of the bacterium. In this study, we have developed a workflow for identification of InhA inhibitors by utilizing in silico virtual screening approaches based on various machine learning algorithms followed by pharmacophore based virtual screening. The hits screened from the models were further subjected to molecular docking. Further, based on the XP docking score best twenty compounds were subjected to molecular dynamics study. Finally, nine compounds were shortlisted on the basis of best stable ligand RMSD, c-alpha RMSD, and RMSF plot for biological evaluation studies. Experimental validation of the shortlisted compounds identified one compound JFD01724 having potent inhibitory activity and was able to inhibit the growth of mycobacterium tuberculosis. Further medicinal chemistry efforts may help to improve the inhibitory potency of the identified compound.

In silico screening of active constituent of Couroupita guianensis against Mycobacterium

Background: A vital need to ascertain novel anti-tubercular agent which is the volatile global spreading of multidrug resistant Mycobacterium tuberculosis. Enoyl-acyl carrier protein reductase is one among such target. It is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. Objective: In this study, in silico evaluations were employed in screening of active constituent of Couroupita guianensis against Enoyl-acyl carrier protein reductase of Mycobacterium tuberculi. Materials and Methods: Totally 16 compounds namely Isatin, Indigo, Coup 2, Indirubin, Calotronaphthalene, Coup, Alpha Amyrin, Nerol, Betasitosterol, Campesterol, Eugenol, Tryptanthrin, Benzyl Alcohol, Betaamyrin and Farnesol were subjected to in silico screening. Glide software of Schrodinger was used to carry out the current work. Results: The compounds exhibit good docking score and few with hydrogen bond interaction. Isoniazid was used as the standard and validation was performed. The results have shown that derivatives were proved to be highly potent inhibitors against Mycobacterium tuberculosis enoyl acyl carrier protein reductase. Conclusion: Most of the compounds exhibit hydrophobic interaction. Then isatin and eugenol can be tested against Mycobacterium tuberculi. Keywords: Couroupita guianensis, Enoyl acyl carrier protein reductase, In silico screening, Mycobacterium tuberculi.

Design, synthesis, evaluation, and molecular dynamic simulation of triclosan mimic diphenyl ether derivatives as antitubercular and antibacterial agents

In the present work, we have explored triclosan mimic diphenyl ether derivatives as inhibitors of Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) using a structure-based drug design approach. The virtual library of diphenyl ethers was designed and compounds with acceptable absorption, distribution, metabolism, excretion, and toxicity properties were docked. The compounds with higher dock score (5a-g) than triclosan were synthesized, characterized, and evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. Among the synthesized compounds, compounds 5f and 5c appeared to be the most promising with minimum inhibitory concentration of 18 μM and 36 μM respectively. The molecular dynamics simulation study of the most active compound 5f and triclosan was performed, which correlates with its activity in comparison with triclosan. All the compounds were further evaluated for cytotoxicity studies against Vero, and HepG2 were found to be safe. Furthermore, compound 5f was evaluated for in vitro cytotoxicity against mouse macrophage cell lines (RAW 264.7), and the study indicated its safety in eukaryotes at 50-μM concentration. In addition, compounds 5a-g were also screened for their in vitro antibacterial activity against two gram-positive and two gram-negative bacteria by resazurin-based microtiter dilution assay method. Among the synthesized compounds, 5f and 5b appeared to be promising, against various gram-positive and gram-negative microorganisms, indicating its broad-spectrum potential.

Structural modification of a novel inhibitor for mycobacterium enoyl-acyl carrier protein reductase assisted by In silico structure-based drug screening.

Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (mtInhA) is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls, and has been targeted in the development of anti-tuberculosis (TB) drugs. In our previous in silico structure-based drug screening study, we identified KES4, a novel class of mtInhA inhibitor. KES4 is composed of four ring structures (A-D-rings) and molecular dynamic simulation predicted that the D-ring is essential for the interaction with mtInhA. The structure-activity relationship study of the D-ring was attempted and aided by in silico docking simulations to improve the mtInhA inhibitory activity of KES4. A virtual chemical library of the D-ring-modified KES4 was then constructed and subjected to in silico docking simulation against mtInhA using the GOLD program. The candidate compound showing the highest GOLD score, referred to as KEN1, was synthesized, and its biological properties were compared with those of the lead compound KES4. We achieved the synthesis of KEN1 and evaluated its effects on InhA activity, mycobacterial growth, and cytotoxicity. The antimycobacterial activity of KEN1 was comparable to that of the lead compound (KES4), although it exhibited superior activity in mtInhA inhibition. \. We obtained a KES4 derivative with high mtInhA inhibitory activity by in silico docking simulation with a chemical library consisting of a series of D-ring-modified KES4.

Synthesis and molecular docking of isonicotinohydrazide derivatives as anti-tuberculosis candidates

Tuberculosis (TB) is a chronic disease as a result of Mycobacterium tuberculosis. It can affect all age groups, and hence, is a global health problem that causes the death of millions of people every year. One of the drugs used in tuberculosis treatment is isonicotinohydrazide (Isoniazid). In this study, N'-benzoylisonicotinohydrazide derivative compounds (a-l) were prepared using acylation reactions between isonicotinohydrazide and benzoyl chloride derivatives, employing the reflux method. Molecular docking studies suggested that all of the compounds had better interaction with Mycobactarium tuberculosis enoyl-acyl carrier protein reductase (InhA) than isonicotinohydrazide. It can be concluded that N'-benzoylisonicotinohydrazide derivatives (a-l) can be used as anti-tuberculosis candidates. The docking results obtained revealed that all of the compounds were interacted well with InhA, with compound g exhibiting the best interaction.

Introducing Broadened Antibacterial Activity to Rhodanine Derivatives Targeting Enoyl-Acyl Carrier Protein Reductase.

Broadened antibacterial activity was introduced to rhodanine derivatives targeting Mycobacterial tuberculosis enoyl-acyl carrier protein reductase (Mtb InhA) by recruiting feature of xacins to bring DNA Gyrase B inhibitory capability. This is significant for preventing further bacterial injections in the tuberculosis treatment. The most potent compound Cy14 suggested comparable bioactivity (IC50 = 3.18 µM for Mtb InhA; IC50 = 10 nM for DNA Gyrase B) with positive controls. Structure-activity relationship discussion and molecular docking model revealed the significance of rhodanine moiety and derived methoxyl on meta-position, pointing out orientations for future modification.