Search Results (16)

Background: Two novel copper(II) coordination complexes, PH-Cu [(1,10-phenanthroline)(malonato)copper(II)] and PC-Cu [(1,10-phenanthroline)(cyclobutane-1,1-dicarboxylato)copper(II)], were synthesized and evaluated as potential anticancer agents, aiming to characterize structural properties, explore antiproliferative activity and generate mechanistic hypotheses through experimental and computational approaches. Methods: Complexes were characterized by EPR, FTIR-ATR, and ESI-MS, with preliminary SC-XRD data for PH-Cu. Antiproliferative activity was evaluated against six human cancer cell lines using the MTT assay (24 h). Subcellular effects were assessed by fluorescence microscopy and RT-qPCR. Computational studies included DFT geometry optimization, target prediction, molecular docking, and ADMET profiling. Results: Based on spectroscopic and spectrometric data and comparison with analogous Cu(II) complexes, a distorted square-pyramidal coordination geometry was proposed; this assignment was not confirmed by SC-XRD. Both complexes exhibited potent antiproliferative activity, with PH-Cu showing the highest potency in HeLa cells (IC₅₀ = 4.22 µM). Under the same conditions, cisplatin showed substantially lower activity (HepG2: 191.1 µM; Caco-2: 129.6 µM; NCI-H69: >333.3 µM; HeLa: 21.9 µM). Fluorescence microscopy at 18 h revealed pyknosis, karyorrhexis, and microtubule disorganization, consistent with regulated cell death. RT-qPCR of PH-Cu indicated intrinsic apoptotic pathway engagement (BAX +3.20-fold; BCL2 to 0.39-fold of control). DFT-optimized bond lengths were consistent with crystallographic data for analogous complexes. Molecular docking suggested PRKCG, RELA (p65), Caspase-3, and α/β-tubulin as interaction candidates, while ADMET profiling predicted favorable intestinal absorption (>92.8%) and low BBB permeability. Conclusions: These results suggest that the [Cu(phen)] unit constitutes the primary pharmacophore, with the dicarboxylate co-ligand as a modulator of the antiproliferative profile, suggesting promising anticancer pharmacological potential. Full article

Background: Oxazolidinone derivatives are a novel class of synthetic antibacterial agents, characterized by a five-membered heterocyclic ring containing oxygen and nitrogen and a carbonyl functionality at position 2. This pharmacophore is responsible not only for antibacterial activity but also for a variety of other biological activities, including anticancer activity, anticoagulant activity, and several others. A series of novel oxazolidinone derivatives containing a hydroxamic acid moiety were synthesized in our laboratories and identified as potent inhibitors of the enzyme 5-lipoxygenase (5-LO), a key enzyme involved in the biosynthesis of leukotrienes (LTs). LTs are proinflammatory mediators implicated in allergic and inflammatory diseases. Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases. This project aims to develop validated stability-indicating analytical methods for the four most potent novel 5-(hydroxamic acid)methyl oxazolidinone derivatives (PH-211, PH-247, PH-249, and PH-251). Methods: The compounds were analyzed using Waters Acquity Ultra-High-Performance Liquid Chromatography (UHPLC-UV) with an ultraviolet detector to determine their stability in human plasma and under various forced degradation conditions, including acidic, basic, oxidative, and thermal conditions. Liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QToF-MS) was used to identify possible degradation products. Results: The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82–90%) but unstable in acidic, basic, and oxidative conditions. Conclusions: The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases. Full article

In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CL^pro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CL^pro–inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CL^pro-IPCL complex (∆∆G_com) and the experimentally determined activities ${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$, which explained approximately 92% of the variation in the 3CL^pro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CL^pro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CL^pro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration ${IC}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CL^pro–inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues. Full article

This study aims to design improved inhibitors targeting the thymidylate kinase (TMK) of Mycobacterium tuberculosis (Mtb), the causative agent of infectious disease tuberculosis that is associated with high morbidity and mortality in developing countries. TMK is an essential enzyme for the synthesis of bacterial DNA. We have performed computer-aided molecular design of MtbTMK inhibitors by modification of the reference crystal structures of the lead micromolar inhibitor TKI1 1-(1-((4-(3-Chlorophenoxy)quinolin-2-yl)methyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione bound to TMK of Mtb strain H37Rv (PDB entries: 5NRN and 5NR7) using the computational approach MM-PBSA. A QSAR model was prepared for a training set of 31 MtbTMK inhibitors with published inhibitory potencies (${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$) and showed a significant correlation between the calculated relative Gibbs free energies of the MtbTMK–TKIx complex formation and the observed potencies. This model was able to explain approximately 95% of the variation in the in vitro inhibition data and validated our molecular model of MtbTMK inhibition for the subsequent design of new TKI analogs. Furthermore, we have confirmed the predictive capacity of this complexation QSAR model by generating a 3D QSAR PH4 pharmacophore-based model. A satisfactory correlation was also obtained for the validation PH4 model of MtbTMK inhibition (R² = 0.84). We have extended the hydrophobic m-chloro-phenoxyquinolin-2-yl group of TKI1 that can occupy the entry into the thymidine binding cleft of MtbTMK by alternative larger hydrophobic groups. Analysis of residue interactions at the enzyme binding site made it possible to select suitable building blocks to be used in the preparation of a virtual combinatorial library of 28,900 analogs of TKI1. Structural information derived from the complexation model and the PH4 pharmacophore guided the in silico screening of the library of analogs and led to the identification of new potential MtbTMK inhibitors that were predicted to be effective in the low nanomolar concentration range. The QSAR complexation model predicted an inhibitory concentration ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ of 9.5 nM for the best new virtual inhibitor candidate TKI 13_1, which represents a significant improvement in estimated inhibitory potency compared to TKI1. Finally, the stability of the MtbTMK–inhibitor complexes and the flexibility of the active conformation of the inhibitors were assessed by molecular dynamics for five top-ranking analogs. This computational study resulted in the discovery of new MtbTMK inhibitors with predicted enhanced inhibitory potencies, which also showed favorable predicted pharmacokinetic profiles. Full article

New antibiotics are unquestionably needed to fight the emergence and spread of multidrug-resistant bacteria. To date, antibiotics targeting bacterial central metabolism have been poorly investigated. By determining the minimal inhibitory concentration (MIC) of desmethylphosphinothricin (Glu-γ-P_H), an analogue of glutamate with a phosphinic moiety replacing the γ-carboxyl group, we previously showed its promising antibacterial activity on Escherichia coli. Herein, we synthetized and determined the growth inhibition exerted on E. coli by an L-Leu dipeptide derivative of Glu-γ-P_H (L-Leu-D,L-Glu-γ-P_H). Furthermore, we compared the growth inhibition obtained with this dipeptide with that exerted by the free amino acid, i.e., Glu-γ-P_H, and by their phosphonic and non-desmethylated analogues. All the tested compounds were more effective when assayed in a chemically-defined minimal medium. The dipeptide L-Leu-D,L-Glu-γ-P_H had a significantly improved antibacterial activity (2 μg/mL), at a concentration between the non-desmethytaled (0.1 μg/mL) and the phosphonic (80 μg/mL) analogues. Also, in Bacillus subtilis, the dipeptide L-Leu-D,L-Glu-γ-P_H displayed an activity comparable to that of the antibiotic amoxicillin. This work highlights the antibacterial relevance of the phosphinic pharmacophore and proposes new avenues for the development of novel antimicrobial drugs containing the phosphinic moiety. Full article

Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum (PfENR) using computer-aided combinatorial and pharmacophore-based molecular design. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) complexation QSAR model was developed for triclosan-based inhibitors (TCL) and a significant correlation was established between the calculated relative Gibbs free energies of complex formation $(∆∆{\mathrm{G}}_{\mathrm{c}\mathrm{o}\mathrm{m}})$ between PfENR and TCL and the observed inhibitory potencies of the enzyme $\left({\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}\right)$ for a training set of 20 known TCL analogues. Validation of the predictive power of the MM-PBSA QSAR model was carried out with the generation of 3D QSAR pharmacophore (PH4). We obtained a reasonable correlation between the relative Gibbs free energy of complex formation ${∆∆\mathrm{G}}_{\mathrm{c}\mathrm{o}\mathrm{m}}$ and ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$ values, which explained approximately 95% of the PfENR inhibition data: ${{p\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}=-0.0544\times {∆∆\mathrm{G}}_{\mathrm{c}\mathrm{o}\mathrm{m}}+6.9336,\mathrm{R}}^2=0.95$. A similar agreement was established for the PH4 pharmacophore model of the PfENR inhibition (${\mathrm{p}\mathrm{I}\mathrm{C}}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}=0.9754\times {\mathrm{p}\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}+0.1596$, ${\mathrm{R}}^2=0.98$). Analysis of enzyme–inhibitor binding site interactions suggested suitable building blocks to be used in a virtual combinatorial library of 33,480 TCL analogues. Structural information derived from the complexation model and the PH4 pharmacophore guided us through in silico screening of the virtual combinatorial library of TCL analogues to finally identify potential new TCL inhibitors effective at low nanomolar concentrations. Virtual screening of the library by PfENR-PH4 led to a predicted ${\mathrm{I}\mathrm{C}}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ value for the best inhibitor candidate as low as 1.9 nM. Finally, the stability of PfENR-TCLx complexes and the flexibility of the active conformation of the inhibitor for selected top-ranking TCL analogues were checked with the help of molecular dynamics. This computational study resulted in a set of proposed new potent inhibitors with predicted antimalarial effects and favourable pharmacokinetic profiles that act on a novel pharmacological target, PfENR. Full article

Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates were presented that combine both opioid and neurotensin pharmacophores in one entity, thus generating a hybrid compound. Importantly, these chimeras are structurally similar except for an amino acid change at position 9 of the peptide chain. In fact, isoleucine (C₆H₁₃NO₂) was replaced with its isomer tert-leucine. These may further lead to various differences in hybrids’ behavior under specific conditions (temperature, UV, oxidative, acid/base environment). Therefore, the purpose of the study is to assess and compare the chemical stability of two hybrid peptides that differ in nature by way of one amino acid (tert-leucine vs. isoleucine). The obtained results indicate that, opposite to biological activity, the substitution of tert-leucine into isoleucine did not substantially influence the compound’s chemical stability. In fact, neither hydrolysis under alkaline and acidic conditions nor oxidative degradation resulted in spectacular differences between the two compounds—although the number of potential degradation products increased, particularly under acidic pH. However, such a modification significantly reduced the compound’s half-life from 204.4 h (for PK20 exposed to 1M HCl) to 117.7 h for [Ile⁹]PK20. Full article

Drug delivery through the Blood–Brain Barrier (BBB) represents a significant challenge. Despite the current strategies to circumvent the BBB, nanotechnology offers unprecedented opportunities for combining selective delivery, improved bioavailability, drug protection, and enhanced pharmacokinetics profiles. Chitosan nanocarriers allow for a more efficacious strategy at the cellular and sub-cellular levels. Boron Neutron Capture Therapy (BNCT) is a targeted chemo-radiotherapeutic technique that allows the selective depletion of cancer cells by means of selective tagging of cancer cells with ¹⁰B, followed by irradiation with low-energy neutrons. Consequently, the combination of a polymer-based nanodelivery system enclosing an effective BNCT pharmacophore can potentially lead to the selective delivery of the load to cancer cells beyond the BBB. In this work, synthesized novel boronated agents based on carborane-functionalized Delocalized Lipophilic Cations (DLCs) are assessed for safety and selective targeting of tumour cells. The compounds are then encapsulated in nanocarriers constituted by chitosan to promote permeability through the BBB. Additionally, chitosan was used in combination with polypyrrole to form a smart composite nanocapsule, which is expected to release its drug load with variations in pH. Results indicate the achievement of more selective boron delivery to cells via carboranyl DLCs. Finally, preliminary cell studies indicate no toxicity was detected in chitosan nanocapsules, further enhancing its viability as a potential delivery vehicle in the BNCT of brain tumours. Full article

In this work, antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) are proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (${ \mathrm{IC}}_{50}^{\exp }$) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure–activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔG_com) and the experimentally measured ${ \mathrm{IC}}_{50}^{\exp }$. Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogues where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictive inhibitory activities falling within the low nanomolar concentration range. Full article

This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs. Full article

Influenza A virus, one of the major human respiratory pathogens, is responsible for annual seasonal endemics and unpredictable periodic pandemics. Despite the clinical availability of vaccines and antivirals, the antigenic diversity and drug resistance of this virus makes it a persistent threat to public health, underlying the need for the development of novel antivirals. In a cell culture-based high-throughput screen, a β2-adrenergic receptor agonist, nylidrin, was identified as an antiviral compound against influenza A virus. The molecule was effective against multiple isolates of subtype H1N1, but had limited activity against subtype H3N2, depending on the strain. By examining the antiviral activity of its chemical analogues, we found that ifenprodil and clenbuterol also had reliable inhibitory effects against A/H1N1 strains. Field-based pharmacophore modeling with comparisons of active and inactive compounds revealed the importance of positive and negative electrostatic patterns of phenyl aminoethanol derivatives. Time-of-addition experiments and visualization of the intracellular localization of nucleoprotein NP demonstrated that an early step of the virus life cycle was suppressed by nylidrin. Ultimately, we discovered that nylidrin targets hemagglutinin 2 (HA2)-mediated membrane fusion by blocking conformational change of HA at acidic pH. In a mouse model, preincubation of a mouse-adapted influenza A virus (H1N1) with nylidrin completely blocked intranasal viral infection. The present study suggests that nylidrin could provide a core chemical skeleton for the development of a direct-acting inhibitor of influenza A virus entry. Full article

Background: During the previous decade a new class of benzamide-based inhibitors of 2-trans enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (Mt) with unusual binding mode have emerged. Here we report in silico design and evaluation of novel benzamide InhA-Mt inhibitors with favorable predicted pharmacokinetic profiles. Methods: By using in situ modifications of the crystal structure of N-benzyl-4-((heteroaryl)methyl) benzamide (BHMB)-InhA complex (PDB entry 4QXM), 3D models of InhA-BHMBx complexes were prepared for a training set of 19 BHMBs with experimentally determined inhibitory potencies (half-maximal inhibitory concentrations IC50exp). In the search for active conformation of the BHMB1-19, linear QSAR model was prepared, which correlated computed gas phase enthalpies of formation (∆∆HMM) of InhA-BHMBx complexes with the IC50exp. Further, taking into account the solvent effect and entropy changes upon ligand, binding resulted in a superior QSAR model correlating computed complexation Gibbs free energies (∆∆Gcom). The successive pharmacophore model (PH4) generated from the active conformations of BHMBs served as a virtual screening tool of novel analogs included in a virtual combinatorial library (VCL) of compounds containing benzamide scaffolds. The VCL filtered by Lipinski’s rule-of-five was screened by the PH4 model to identify new BHMB analogs. Results: Gas phase QSAR model: −log₁₀(IC₅₀^exp) = pIC₅₀^exp = −0.2465 × ∆∆H_MM + 7.95503, R² = 0.94; superior aqueous phase QSAR model: pIC₅₀^exp = −0.2370 × ∆∆G_com + 7.8783, R² = 0.97 and PH4 pharmacophore model: $p{{\mathrm{IC}}_{50}}^{\exp }$ = 1.0013 × p ${{\mathrm{IC}}_{50}}^{\exp }$ − 0.0085, R² = 0.95. The VCL of more than 114 thousand BHMBs was filtered down to 73,565 analogs Lipinski’s rule. The five-point PH4 screening retained 90 new and potent BHMBs with predicted inhibitory potencies IC₅₀^pre up to 65 times lower than that of BHMB1 (IC₅₀^exp = 20 nM). Predicted pharmacokinetic profile of the new analogs showed enhanced cell membrane permeability and high human oral absorption compared to current anti-tuberculotics. Conclusions: Combined use of QSAR models that considered binding of the BHMBs to InhA, pharmacophore model, and ADME properties helped to recognize bound active conformation of the benzamide inhibitors, permitted in silico screening of VCL of compounds sharing benzamide scaffold and identification of new analogs with predicted high inhibitory potencies and favorable pharmacokinetic profiles. Full article

Research on neurodegenerative brain disorders, namely the age-dependent Alzheimer’s disease (AD), has been intensified in the last decade due to the absence of a cure and the recognized increasing of life expectancy for populations. To address the multifactorial nature and complexity of AD, a multi-target-directed ligand approach was herein employed, by designing a set of six selected hybrids (14–19) that combine in the same entity two pharmacophores: tacrine (TAC) and 2-phenylbenzothiazole (PhBTA). The compounds contain a methoxy substituent at the PhBTA moiety and have a variable length linker between that and the TAC moiety. The docking studies showed that all the compounds assure a dual-binding mode of acetylcholinesterase (AChE) inhibition, establishing π-stacking and H-bond interactions with aminoacid residues at both active binding sites of the enzyme (CAS and PAS). The bioassays revealed that the designed compounds display excellent AChE inhibitory activity in the sub-micromolar range (0.06–0.27 μM) and moderate inhibition values for amyloid-β (Aβ) self-aggregation (27–44.6%), compounds 14 and 15 being the lead compounds. Regarding neuroprotective effects in neuroblastoma cells, compounds 15, 16 and 19 revealed capacity to prevent Aβ-induced toxicity, but compound 16 showed the highest neuroprotective effect. Overall these hybrid compounds, in particular 15 and 16, with promising multitarget anti-AD ability, encourage further pursuing studies on this type of TAC-PhBTA derivatives for potential AD therapy. Full article

Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give 1,3,5-pyridinium salts. The reaction, carried out at pH 6, provides conditions suitable for the use of less stable aldehydes and amines in this Chichibabin pyridine condensation. The evaluation of selected 1,3,5-trisubstituted pyridinium salts highlighted that they can inhibit the growth of S. aureus in the low μg/mL range. The synthetic accessibility of these compounds and preliminary growth inhibition data may pave the way towards the discovery of new anti-bacterials based on the 1,3,5-trisubstituted pyridinium scaffold. Full article

We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC₅₀^exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC₅₀^exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔG_com) of InhA-PCAM complex formation and IC₅₀^exp (pIC₅₀^exp = −0.1552·ΔΔG_com + 5.0448, R² = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC₅₀^pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles. Full article