Potential Antitubercular Agents Research Articles

Pyrazole-coumarin and pyrazole-quinoline chalcones as potential antitubercular agents.

Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study, two series of novel pyrazole-coumarin chalcones and pyrazole-quinoline chalcones were synthesized using multiple-step reactions. All the synthesized compounds were well characterized using different spectroscopic techniques including 1 H and 13 C nuclear magnetic resonance, high-resolution mass spectroscopy, and electrospray ionization-mass spectrometry. The compounds were evaluated for their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain using the microplate Alamar Blue assay, and the minimal inhibitory concentrations (MIC) of the compounds were determined. Among the 32 tested compounds, compounds 3e, 3u, and 7h showed an MIC value of 3.125µg/ml, and they were found to be nontoxic. Molecular docking studies of the compounds with the enzyme DprE1 revealed the probable mechanism of action. The chalcone derivatives exhibited binding affinity values between -7.047 and -9.353 kcal/mol. ADME parameters were predicted using the QikProp module of the Schrödinger software, and these compounds exhibited good pharmacological and oral absorption properties.

Indole-fused spirochromenes as potential anti-tubercular agents: design, synthesis and in vitro evaluation.

As part of an ongoing effort to develop new anti-tubercular agents, a series of novel indole-fused spirochromene hybrids (7a-l) were efficiently synthesized in excellent yields by the popular 'Fisher-Indole synthesis' approach. The structure elucidation of the target compounds was carried out by different spectral techniques including 1H-NMR, 13C-NMR, ESI Mass, and FTIR analysis. Additionally, the proposed structure of 7i was proved by single-crystal X-ray analysis. These compounds (7a-l) were screened for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. The results showed that most of the targets exhibited promising antimycobacterial activity with MICs of 1.56-6.25μg/mL and weak cytotoxicity (19.93-32.16% at 50μg/mL). Among them, compound 7l was found to be the most active compound (MIC of 1.56μg/mL) with a good safety profile (32.16% at 50μg/mL).

Novel Furan Coupled Quinoline Diamide Hybrid Scaffolds as Potent Antitubercular Agents: Design, Synthesis and Molecular Modelling.

A novel series of 2-[(2-{[2-(furan-2-yl) quinolin-4-yl] carbonyl} hydrazinyl) carbonyl] benzoic acid, -4-oxobut-2-enoic acid and -4-oxobutanoic acids were synthesized and screened for in vitro antitubercular activity. In the present investigation, we describe the synthesis and biological screening of furan C-2 quinoline coupled diamides for antitubercular activity. The mycobacterium tuberculai testing was carried out by MABA method and molecular docking studies were done by open-source molecular docking program, Autovina, using Pyrx 0.8 interface. The results revealed that the compounds inhibited the growth of H37Rv strain at concentrations as low as 1.6 to 12 µg/ml. Molecular binding of furan, quinoline and diamide (FQD) derivatives on five targets was good and these compounds fit very well within the binding domain of the target protein. The synthesized FQD derivatives exhibited moderate to good inhibition activity especially compounds 5f, 5b and 8a exhibited very good inhibition activity due to the presence of three different scaffolds, such as INH, phenyl ketobutyric acid and fluoroquinolines. Hybridized molecules might have multiple modes of action / inhibit more than one tubercular target and could pave way for novel drug discovery in the field of tuberculosis.

Discovery of 1,2,3-triazole based quinoxaline-1,4-di-N-oxide derivatives as potential anti-tubercular agents.

A series of thirty one novel 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-3-methylquinoxaline-1,4-dioxide (7a-l), 3-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6-chloro-2-methylquinoxaline-1,4-dioxide (8a-l) and 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6,7-dichloro-3-methylquinoxaline-1,4-dioxide (9a-g) analogues were synthesized, characterized using various analytical techniques and single crystal was developed for the compounds 8g and 9f. Synthesized compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two clinical isolates Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 30.35 to 252.00µM. Among the tested compounds, 8e, 8l, 9c and 9d exhibited moderate activity (MIC=47.6 - 52.0µM) and 8a exhibited significant anti-tubercular activity (MIC=30.35µM). Furthermore, 8e, 8l, and 9d were found to be less toxic against human embryonic kidney, HEK 293 cell lines. Finally, a docking study was also performed using MTB DNA Gyrase (PDB ID: 5BS8) for the significantly active compound 8a to know the exact binding pattern within the active site of the target enzyme.

Theoretical investigation of a few selected compounds as potent anti-tubercular agents and molecular docking evaluation: A multi-linear regression approach

Emergence of multi-drug resistant strains of Mycobacterium tuberculosis to the available drugs has demanded for the development of more potent anti-tubercular agents with efficient pharmacological activities. Time consumed and expenses in discovering and synthesizing new drug targets with improved biological activity have been a major challenge toward the treatment of multi-drug resistance strain M. tuberculosis. To solve the above problem, Quantitative Structure Activity Relationship (QSAR) is a recent approach developed to discover a novel drug with a better biological against M. Tuberculosis. A validated QSAR model developed in this study to predict the biological activities of some anti-tubercular compounds and to design new hypothetical drugs is influenced with the molecular descriptors; AATS7s, VR1-Dzi, VR1-Dzs, SpMin7-Bhe and RDF110i. The internal validation test for the derived model was found to have correlation coefficient (R2) of 0.8875, adjusted correlation coefficient (R2adj) value of 0.8234 and leave one out cross validation coefficient (Qcv2) value of 0.8012 while the external validation test was found to have (R2test) of 0.7961 and Y-randomization Coefficient (cRp2) of 0.6832. Molecular docking shows that ligand 13 of 2,4-disubstituted quinoline derivatives have promising higher binding score of -18.8 kcal/mol compared to the recommended drugs; isoniazid -14.6 kcal/mol. The proposed QSAR model and molecular docking studies will provides valuable approach for the modification of the lead compound, designing and synthesis more potent anti-tubercular agents.

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

The objective of our current study is to design and synthesise more potent hydrazide- hydrazones, containing anti-tubercular agents. 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). 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. 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.

Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents

Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure–activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc1 complex. In addition, leading compounds were devoid of apparent toxicity to HepG2 and Vero cells and showed moderate elimination rates in human liver S9 fractions. Finally, the selected structures inhibited M. tuberculosis growth in a macrophage model of tuberculosis infection. Taken together, these data indicate that this class of compounds may furnish candidates for the future development of antituberculosis drugs.

New Insights in Design and Development of Antitubercular Drugs

Background: Tuberculosis, an infectious disease caused mainly by the Mycobacterium tuberculosis accounts for the highest number of deaths worldwide. Despite curing millions, the currently used drug regimens are bounded by various limitations such as long course of therapy, emergence of resistance and permanent tissue damage. The treatment of multidrug-resistant and extremely drugresistant tuberculosis is a challenging task due to its reliance on second-line drugs which are less potent and more toxic than those used in the clinical management of drug-susceptible tuberculosis. Therefore, the major challenges in the upcoming years are to overcome the emergence of increased number of multidrug-resistant as well as extensively drug-resistant strains and the ineptness of the current treatment regimens against latent tuberculosis. Bedaquiline and Delamanid are the only new anti-TB drugs that have been currently approved since more than 40 years after discovery of isoniazid. Bedaquiline is the first diarylquinoline derivative that has showed resilient culture conversion at 24 weeks in phase IIb trials. Methods: Extensive literature search on the topic was undergone using a focused question. Results: Fifty-eight research articles from journals of repute are included in the review. The vaccine and peptide-based conjugates are recent developments against Mycobacterium for selective and specific targeting to the desired tissues. Conclusion: In this review, we have focused on the different classes of chemical as well as plant based compounds as potent antitubercular agents against multidrug-resistant tuberculosis strains. This review falls light on the importance of research been undergoing in different parts of the world to combat the ever increasing problem of mycobacterial resistance and the various treatment options available for the treatment of tuberculosis.

N-Mannich bases of benzimidazole as a potent antitubercular and antiprotozoal agents: Their synthesis and computational studies

This article dealing with the microwave assisted synthesis of N-Mannich bases of pyridine clubbed with two different benzimidazole cores with their micromolar biological potency. All the synthesized compounds were evaluated for their in-vitro antibacterial, antimycobacterial and antiprotozoal potency. One of the final compound was found to be most active against M. tuberculosis (MIC = 3.125 µM) in the primary screening. N-Mannich bases of benzimidazole with pyridine-3-amine and 5-methyl-pyridine-2-amine showed potency against L. mexicana and T. cruzi respectively with IC50 value 0.25 and 1.02 µg/mL. Compound 4a showed good binding energy in the active pocket of receptor (PDB: 4cod) with −11.013 docking score. The stability of docked complex was validated by performing Molecular dynamics (MD) up to 20 ns simulation time. In silico ADME parameters and toxicity predicted that the active compounds belong to the Class IV GHS with LD50 value 1360 mg/kg and hence found to be mildly toxic.

4-Substituted picolinohydrazonamides as a new class of potential antitubercular agents

The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4–0.8 μg/mL) was higher than that of reference drugs. Moreover, derivative 15 exhibited lower activity against other tested microorganism such as bacteria gram-positive, gram-negative or fungi. Thus, this compound is characterized by the selectivity of antimicrobial activity. Antiproliferative study conducted against human dermal fibroblasts (HDF) and mouse melanoma cell line (B16-F10) revealed low cytotoxicity of compound 15. Conducted research allowed to identify compound 15 as leading for further research.

Synthesis and biological evaluation of some 4-aminoquinoline derivatives as potential antitubercular agents

BackgroundBased on bioisosteric similarities with thiacetazone, a series of 7-chloro-4-aminoquinoline derivatives have been designed and synthesized. The target compounds were elucidated by NMR, mass, and FTIR spectral data. All synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (MTB), and human dermal fibroblast cell lines were used to assess toxicity of selected ligands.ResultsAll of the designed compounds showed inhibition of MTB with MIC of 1.56–50 μM. Among the tested compounds, 7c and 7g proved to be most potent MTB inhibitors (MIC = 1.56 μM).ConclusionsThe outcome of present study suggests that most of the synthesized compounds are sensitive to Mycobacterium tuberculosis and showed acceptable range for molecular parameters. Thus, 7-chloro-4-aminoquinolines could be a useful lead for the development of new MTB inhibitory agents.

Multi-linear regression model, molecular binding interactions and ligand-based design of some prominent compounds against Mycobacterium tuberculosis

Multidrug-resistant strains of Mycobacterium tuberculosis still remain a major challenge in creating first-hand drugs for treating tuberculosis. Development and syntheses of novel compounds with more potent anti-tubercular agents are usually by the trial and error approach which is time consuming and expensive. QSAR is a theoretical approach which has the potential to reduce the aforementioned problem in discovering new potent drugs against M. Tuberculosis. This approach was employed to develop the multivariate QSAR model to correlate the chemical structures of the 1,2,4-triazole analogues with their observed activities using a theoretical approach. To build the robust QSAR model, genetic function approximation was employed as a tool for selecting the best descriptors that could efficiently predict the activities of the inhibitory agents. The developed model was influenced with molecular descriptors, AATS7s, nHBint3, minHCsatu, TDB9e, RDF90i and RDF110s which have been validated through internal and external validation tests. Molecular docking studies were also carried for all the studied compounds to show the interactions and binding modes between the ligand and the receptor (DNA gyrase). The lead compound (compound 34) with higher anti-tubercular activity was observed with prominent binding affinity of 21.9 kcal/mol compared to the recommended drugs: isoniazid (− 14.6 kcal/mol) and ethambutol (− 5.8 kcal/mol). Therefore, compound 34 served as a template structure to designed compounds with more efficient activities. Among the compounds designed, compounds 34p, 34q and 34r were observed with better anti-tubercular activities with more prominent binding affinities which ranges from − 24.3 to − 28.6 kcal/mol. The outcome of this research is recommended for pharmaceutical and medicinal chemists to synthesize and carry out an in vivo and in vitro screening for the proposed designed compounds to substantiate the computational findings.

Synthesis, Characterization and Docking Studies of N-Methyl-2, 3-Dihydro Quinazolin-4-Ones Linked 1,3-Thiazole Hybrids as Potent Anti-Tubercular Agents

Quinazolin-4-ones connected 1, 3-thiazole were found with antibacterial action after high throughput screening. N-Methyl Anthranilic acid when treated with thiophene-2-carboxylic acid gives 1-Methyl-2- (thiophen-2-yl)-1,2-dihydro-4H-3,1-Benzoxazin-4-one which on further treatment with 4-substituted phenyl-1,3-thiazol-2-amines gives 1-Methyl-3-(4-Substituted phenyl-1,3-thiazol-2yl)-2-(thiophen-2-yl)-2,3- dihydro quinazoline-4(1H)-ones (5Fa1-5Fk11) were obtained. The structural identification was done through Infra-red, 1H- Nuclear magnetic resonance, 13C- Nuclear magnetic resonance, and Mass spectrometry. These derivatives were screened for anti-tubercular activity against Mycobacterium tuberculosis H37RV using the micro plate alamar blue assay method. Compounds 5Ff6, 5Fe5, 5Fb2, and 5Fd4 displayed better antibacterial activity at minimum inhibitory concentration 12.5 and 6.25 μg/ml. Further, 5Ff6 displayed a favourable inhibition at minimum inhibitory concentration 6.25 μg/ml, contrasted with the reference drug Isoniazide. The compounds were docked where they exhibited associations with both the vital site of penicillin-binding protein 2a and Mycobacterium tuberculosis H37Rv organism. All the derivatives showed good affinity towards the protein when compare with the standard drug. Here 5Ff6 was observed to interact with three amino acids, viz., Agn104, Lys273, and Tyr297, as signified by the great interaction energy (ΔG=-4.2 kcal/mol).

Synthesis, Characterization, Screening and Docking Studies of Some Novel 5-Chloro benzimidazole-2-one Derivatives as Potent Antitubercular Agents

A series of 5-chloro-1-(piperidin-4-yl)-1H-benzo[d]imidazole-2(3H)-one derivatives have been synthesized and characterized by various spectroscopic techniques including FTIR, mass and 1H NMR. In current study, we have followed standard methods for the synthesis of novel molecules, docking and screening against mycobacterium species. The compounds were docked against 2Q1Y protein by using MCULE software and screened them by MABA. Out of sixteen synthesized molecules, two molecules i.e. DSR-14 and DSR-9 had shown good antitubercular activity.

Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents.

Pyrazinamide is an important first-line drug used in shortening TB therapy. In our current work, a series of novel substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra. Among the tested compounds, five compounds (6a, 6e, 6h, 6j and 6k) from Series-I and one compound (7e) from Series-II exhibited significant activity against Mycobacterium tuberculosis H37Ra with 50% inhibitory concentrations (IC50) ranging from 1.35 to 2.18 μM. To evaluate the efficacy of these compounds, we examined their IC90 values. Five of the most active compounds were found to be more active with IC90s ranging from 3.73 to 4.00 μM and one compound (6e) showed an IC90 of 40.32 μM. Moreover, single crystals were developed for 6d, 6f and 6n. In addition, most active compounds were evaluated for their cytotoxicity on HEK-293 (human embryonic kidney) cells. Our results indicate that the compounds are nontoxic to human cells. The molecular interactions of the derivatised conjugates in docking studies reveal their suitability for further development.

The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles

Tuberculosis remains as a major public health risk which causes the highest mortality rate globally and an improved regimen is required to treat the drug-resistant strains. Pyrazinamide is a first-line antitubercular drug used in combination therapy with other anti-TB drugs. Herein, we describe the modification of pyrazinamide structure using bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for their in vitro inhibitory potency against mycobacterium tuberculosis H37Rv. The pyrazine-1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds, seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56 μg/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well. Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME prediction revealed good oral bioavailability for the potent molecules.

Design, Molecular Docking and In-Silico Analysis of Novel thiadiazole-azetidinone hybrids as Potential Antitubercular Agents

The recent emergence of extensively drug-resistant tuberculosis has become a cause of concern for the management of tuberculosis globally. Shikimic acid pathway seems to be a potential and favorable target for the drug design of new anti-infective agents. This work aims to change the focus from traditional cell approaches to the target-based design of novel thiadiazolyl-azetidinone derivatives with Shikimate kinase as the drug target for anti-tubercular activity. Thiadiazole and azetidinone derivatives were methodically reprised to design a series of 3-chloro-4-(aryl)-1-(5-sulfanyl-1,3,4-thiadiazol-2-yl)azetidin-2-one derivatives (AZ1-AZ12). Molecular docking studies were performed on a crystal model of Mycobacterium tuberculosis Shikimate kinase (MtSK) using Vlife MDS 4.4 suite to evaluate their anti-tubercular potential. Further, drug-likeness properties and ADMET prediction were performed by molinspiration and admetSAR software to better describe the designed molecules as prospective candidates. 3-chloro-4-(4-nitrophenyl)-1-(5-sulfanyl-1,3,4-thiadiazol-2-yl)azetidin-2-one (AZ3), was found to be have better dock score when compared with the natural substrate, Shikimate. Docking studies confirmed that the molecules showed significant binding in the active site region of Shikimate kinase. Strong hydrogen bonding and hydrophobic interactions with amino acid residues and other parameters further explicate their effectiveness for inhibition of MtSK. Also, the physicochemical properties and drug scores for the designed compounds obtained by in silico studies were found to be satisfactory, signifying the overall potential of the designed molecules to be drug candidates. Thus these molecules could be explored as a lead for further anti-tubercular studies with Mycobacterium tuberculosis Shikimate kinase as the drug target.

Synthesis, bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1,2,3-triazoles

In search of more potent new antitubercular agents, a library of novel piperazine tethered dimeric 1,2,3-triazoles were designed by assembling 1,2,3-triazoles and piperazine in a single molecular architectural framework. The titled compounds (3a–m) were synthesized by 1,3-dipolar cycloaddition of 1,4-di(prop-2-yn-1-yl)piperazine (1) and various azides (2a–m) using click chemistry approach with good yields. All the synthesized compounds (3a–m) have been screened for their in vitro antitubercular, antifungal and antioxidant activities against their respective strains. Among them, 3b, 3d, and 3i have revealed promising antitubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv with MIC 12.5 µg/mL. Molecular docking results provided well-clustered solutions to the mode of binding for these molecules into the active site of Mtb enoyl reductase (InhA). In addition to this, most of synthesized compounds were found to have potential antifungal as well as antioxidant activity.

Design, synthesis, in silico and in vitro evaluation of novel diphenyl ether derivatives as potential antitubercular agents.

Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors using molecular modelling, a cross-docking and correlation study was performed. A series of novel 1-(3-(3-hydroxy-4-phenoxyphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl) ethan-1-ones were synthesized from this model and screened for their antitubercular activity against M. tuberculosis H37Rv. Compound PYN-8 showed good antitubercular activity on M. tuberculosis H37Rv (MIC = 4-7µM) and Mycobacterium bovis (% inhibition at 10µM = 95.91%). Cytotoxicity of all the synthesized derivatives was assessed using various cell lines, and they were found to be safe. Structure of PYN-8 was also confirmed by single-crystal X-ray diffraction. The molecular modelling studies also corroborated the biological activity of the compounds. Further, in silico findings revealed that all these tested compounds exhibited good ADME properties and drug likeness and thus may be considered as potential candidates for further drug development.

Strategically Placed Trifluoromethyl Substituent in the Realm of Antitubercular Drug Design

Background:Fluorinated substituents have played, and continue to play an important role in antitubercular drug design. Nonetheless, previous works have indicated that organofluorines like –F, CF3, -OCF3, and CHF2 etc have been used to modulate the pharmacodynamic and pharmacokinetic behaviour of antitubercular agents. Among the fluorinated groups, trifluoromethyl (-CF3) substituent is a very familiar pharmacophore used widely in antitubercular research.Objective:This review assesses the development of selected trifluoromethyl group bearing antitubercular agents that are either in treatment or considered to be potential. The prime objective of the present investigation was to provide initial evidences for the hypothesis that addition of trifluoromethyl group to antiTB agents could improve their potency. We also aimed to contribute to a better understanding of the role of trifluoromethyl group on drug-likeness antitubercular activity.Methods:In this review, we first brief out the possible effect of –CF3 substituent on pharmacodynamic and pharmacokinetic properties of drugs. Next, we turn to emphasize on the effect of trifluoromethyl substituent on different antitubercular scaffolds. Finally, we open the topic for the researchers to design potential antitubercular agents suitably substituted with fluorinated groups.Results:This review suggests that the replacement of –CF3 group in heterocyclic as well as phenyl ring led to the improvement in pharmacodynamic and pharmacokinetic properties of the compounds. Hence it's not surprising to see –CF3 group emerging as an alternative electron withdrawing group instead of halogens in many promising antitubercular agents.Conclusion:This unusual spectrum of advantage allied with its lipophilicity enhancing effect, made –CF3 group distinct from other substituents in modern antitubercular drug design. The present study provides conceptual advances to the understanding of the physicochemical properties of –CF3 group and its effect on antitubercular activity.