Promising Antitubercular Activity Research Articles

Development and Evaluation of Bis-benzothiazoles as a New Class of Benzothiazoles Targeting DprE1 as Antitubercular Agents.

Benzothiazole-bearing compounds have emerged as potential noncovalent DprE1 (decaprenylphosphoryl-β-d-ribose-2'-epimerase) inhibitors active against Mycobacterium tuberculosis. Based on structure-based virtual screening (PDB ID: 4KW5), a focused library of thirty-one skeletally diverse benzothiazole amides was prepared, and the compounds were assessed for their antitubercular activity against M.tb H37Ra. Most potent compounds 3b and 3n were further evaluated against the M.tb H37Rv strain by the microdilution assay method. Among the compounds evaluated, bis-benzothiazole amide 3n emerged as a hit molecule and demonstrated promising antitubercular activity with minimum inhibitory concentration (MIC) values of 0.45 μg/mL and 8.0 μg/mL against H37Ra and H37Rv, respectively. Based on the preliminary hit molecule (3n), a focused library of 12 more bis-benzothiazole amide derivatives was further prepared by varying the substituents on either side to obtain new leads and generate a structure-activity relationship (SAR). Among these compounds, 6a, 6c, and 6d demonstrated remarkable antitubercular activity with MIC values of 0.5 μg/mL against H37Ra and 1.0, 2.0, and 8.0 μg/mL against H37Rv, respectively. The most active compound, 6a, also displayed significant efficacy against four drug-resistant tuberculosis strains. Compound 6a was assessed for in vitro cytotoxicity against the HepG2 cell line, and it displayed insignificant cytotoxicity. Furthermore, time-kill kinetic studies demonstrated time- and dose-dependent bactericidal activity of this compound. The GFP release assay revealed that compound 6a targets the inhibition of a cell wall component. SNPs in dprE-1 gene assessment revealed that compound 6a binds to tyrosine at position 314 of DprE1 and replaces it with histidine, causing resistance similar to that of standard TCA1. In silico docking studies further suggest that the strong noncovalent interactions of these compounds may lead to the development of potent noncovalent DprE1 inhibitors.

Synthesis of Naphtho[1′,2′4,5]imidazo[2,1‐b]thiazoles via CuCl‐Catalyzed Cross‐Coupling of Ethynylimidazothiazoles With N‐tosyl Hydrazones and Their Antitubercular Activity

AbstractDescribed herein is a tandem reaction involving a copper chloride‐catalyzed cross‐coupling and an allene‐mediated cyclization of substituted ethynylimidazo[2,1‐b]thiazoles with aromatic N‐tosylhydrazones, producing naphtho[1′,2′4,5]imidazo [2,1‐b]thiazoles in very good yields. This protocol offers the advantages of one‐pot conversion from stable and readily available substrates as well as good functional group compatibility to prepare polycyclic N‐fused heteroaromatic systems. Moreover, the new compounds exhibited promising antitubercular activity.

Synthesis, Activity, Toxicity, and In Silico Studies of New Antimycobacterial N-Alkyl Nitrobenzamides.

Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-β-D-ribofuranose 2'-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1.

Dual Antitubercular and Antileishmanial Profiles of Quinoxaline Di-N-Oxides Containing an Amino Acidic Side Chain.

We present a new category of quinoxaline di-N-oxides (QdNOs) containing amino acid side chains with dual antituberculosis and antileishmanial activity. These compounds were synthesized by combining a regioselective 2,5-piperazinedione opening and a Beirut reaction and were screened for their activity against Mycobacterium tuberculosis and the promastigote and amastigote forms of representative species of the Leishmania genus. Most QdNOs exhibited promising antitubercular activity with IC50 values ranging from 4.28 to 49.95 μM, comparable to clinically established drugs. Structure-activity relationship analysis emphasized the importance of substituents on the aromatic ring and the side chain. Antileishmanial tests showed that some selected compounds exhibited activity comparable to the positive control miltefosine against promastigotes of Leishmania amazonensis and Leishmania donovani. Notably, some compounds were found to be also more potent and less toxic than miltefosine in intracellular amastigote assays against Leishmania amazonensis. The compound showing the best dual antitubercular and leishmanicidal profile and a good selectivity index, 4h, can be regarded as a hit compound that opens up new opportunities for the development of integrated therapies against co-infections.

Synthesis and In vitro Screening of Pyrazine-2-Carbohydrazide Derivatives as Potential Antimicrobial Agents

Herein, we report the design of a new set of pyrazine-2-carbohydrazide derivatives (T1–T20) and in silico investigations to evaluate their inhibition activity against the enzyme, decaprenylphosphoryl-[Formula: see text]-D-ribose 2′-epimerase (DprE1). The derivatives interact with the Cys387 residue of the enzyme’s active site through hydrogen bonds. Further, we synthesized these compounds and evaluated their efficacy against the M. tuberculosis H37Rv strain. Compounds T16 and T19 displayed promising antitubercular activity, boasting a minimal inhibitory concentration of 1.56 [Formula: see text]g/mL. Furthermore, we assessed the antibacterial activity of these compounds against a range of pathogens, including S. aureus, S. mutans, E. coli and [Formula: see text]Typhi. Additionally, we evaluated their antifungal potency against A. niger. Notably, compounds T4, T8, T9, T16 and T19 exhibited noteworthy antibacterial activity against tested bacterial strains. Compounds T4, T9, T16, T17, T18 and T19 showed significant inhibition activity against A. niger. Importantly, all active compounds demonstrated low cytotoxicity, with IC50 values exceeding 300 [Formula: see text]M, ensuring no harm to normal cells. To gain a deeper understanding of these compounds, we conducted in silico investigations to evaluate their pharmacokinetics and pharmacochemical properties. Additionally, we employed DFT studies to explore the electronic characteristics of these compounds, providing valuable insights into their potential applications in the pharmaceutical field.

Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment.

In this study, we present a novel series of (E)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((E)-(((Z)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the M. tuberculosis H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing S. aureus, B. subtilis, S. mutans, E. coli, S. typhi, and K. pneumoniae. Additionally, their antifungal efficacy against A. fumigatus and A. niger also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.

Synthesis and antibacterial activity of 6″-decanesulfonylacetamide-functionalised amphiphilic derivatives of amikacin and kanamycin

Aminoglycoside antibiotics represent the first class of successful drugs in the treatment of tuberculosis; however, mycobacteria and other bacterial species possess several drug resistance mechanisms to inactivate these natural products. In the past 15 years, a variety of amphiphilic aminoglycosides have been shown to have improved activity against infectious microorganisms and to subvert resistance mechanisms. Here, we report on four novel synthetic compounds derived from two existing potent antitubercular compounds and describe their activity against both Mycobacterium tuberculosis and Staphylococcus aureus. It was found that a decanesulfonylacetamide-based conjugate of amikacin displayed promising preliminary antitubercular activities, warranting further investigation to assess the therapeutic potential of these unique antimicrobials.

Targeting AKT2 in MDA-MB-231 Cells by Pyrazole Hybrids: Structural, Biological and Molecular Docking Studies.

Pyrazolic hybrids appended with naphthalene, p-chlorobenzene, o-phenol and toluene have been synthesized using Claisen Schmidt condensation reaction of 1-benzyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. All compounds were characterized by various spectroscopic techniques. Compound (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one crystallizes in monoclinic crystal system with C2/c space group. These synthesized compounds were tested for cytotoxic activity and among these compounds 4b and 5a shows prominent cytotoxic activity against triple-negative breast cancer (TNBC) cells MDA-MB-231 with IC50 values 47.72 μM and 24.25 μM, respectively. Distinguishing morphological changes were noticed in MDA-MB-231 cells treated with pyrazole hybrids contributing to apoptosis action. To get more insight into cytotoxic activity, in silico molecular docking of these compounds were performed and the results suggested that (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(p-tolyl)prop-2-en-1-one and 1-(1'-benzyl-5-(4-chlorophenyl)-3',5'-dimethyl-3,4-dihydro-1'H,2H-[3,4'-bipyrazol]-2-yl)ethan-1-one binds to the prominent domain of Akt2 indicating their potential ability as Akt2 inhibitor. Moreover, from in silico ADME studies clearly demonstrated that these compounds may be regarded as a drug candidate for sub-lingual absorption based on log p values (2.157-4.924). These compounds also show promising antitubercular activity. The overall results suggest that pyrazolic hybrids with substitution at less sterically hindered positions have appealing potent cytotoxic activity and antituberculosis activity due to which they may act as multidrug candidate.

Analog-based Design and Development of Novel Molecules as Anti-tubercular Agents

Abstract: Background: The burden of tuberculosis is immense as most of the drugs developed resistance to Mycobacterium tuberculosis (Mtb). This issue shall be addressed by developing new drugs acting through novel mechanisms. GSK 2556286 (GSK-286) is a phase 1 clinical candidate with a novel mechanism of action related to cholesterol catabolism, hence it was selected as template/ parent molecules for our analogue-based drug design strategy. Materials and Methods: The novel-designed molecules were initially checked to be drug-like using ‘Lipinski’s rule of five and synthesized with good yields. The obtained compounds were evaluated for anti-tubercular activity against Mtb H37Rv, antibacterial activity against S. aureus and E. coli, cytotoxicity screening against mammalian VERO cells and BBB permeability against Porcine Brain Lipid. Docking was also performed against HsaA monooxygenase (PDB ID: 3AFF) to understand the possible mechanism of action. Results and Conclusion: The compounds 3a and 7a exhibited promising anti-tubercular activity at MIC of 3.13 μg/mL. Further, the compounds proved to be effective towards S. aureus at 0.98 μg/mL and E. coli at 7.81 μg/mL. The molecules 3a and 7a produced good docking scores of -9.2 and -9.3 kcal/mole respectively. The association between docking results and anti-tubercular activity has postulated that the molecules could act through novel mechanisms by inhibiting HsaA monooxygenase. Moreover, all the compounds in the study produced very less cytotoxicity at CC50 > 190 μg/mL against mammalian VERO cells and also showed minimal BBB permeability in PAMPA assay. The effective anti-tubercular activity of the lead molecules with additional safety against mammalian VERO cells with reduced BBB permeability could provide a new standpoint in anti-tubercular drug discovery. Keywords: Analog-based Design, Anti-tubercular activity, BBB permeability, GSK 2556286, VERO cells.

Design, Synthesis, Anti-tubercular and Docking Studies of Novel 2-Furanyl-3-substituted Quinazolin-4-one Derivatives

In this work, the synthesis, characterization and the anti-tubercular activity of novel 2-furanyl-3- substituted quinazolin-4-one derivatives and also predicted their affinity against Mycobacterium tuberculosis enoyl acyl carrier protein reductase were carried out. The targeted compounds were synthesized by the condensation of 2-(furan-2-yl)-4(3H)-1-benzoxazine-4-one with different primary amines. After structural elucidation using spectral data, the compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37RV strain. The binding affinity against enoyl acyl carrier protein reductase was predicted using MOE and FITTED docking tools. The synthesized compounds showed a promising anti-tubercular activity in the range from 12.5 to 100 μg/mL. According to MOE docking, the common amino acids in the active site of InhA were found to form hydrogen bonding and hydrophobic interactions with the synthesized quinazolinones. Docking simulations also showed that an aromatic side chain capable of forming hydrogen bond interactions can increase affinity of 2-furanyl quinazolinones to enoyl acyl carrier protein reductase.

Novel fluorophenyl tethered thiazole and chalcone analogues as potential anti-tubercular agents: Design, synthesis, biological and in silico evaluations

Novel analogues of fluorophenyl tethered thiazoles 7a-k and chalcones 10a-k were designed through molecular hybridization approach. All the synthesized final compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Rv strain. Among the two series, compound 10g displayed potent inhibition with MIC99 of 1.56 µM against parental and isoniazid-resistant strains of M. tuberculosis. Further, the same compound inhibited the growth of intracellular M. tuberculosis. To gain an insight into the molecular mechanism of actions, in silico molecular docking experiments were conducted using the molecular structure of the DNA gyrase enzyme, which revealed crucial interactions. This was further substantiated through molecular dynamics simulation study of the mycobacterial DNA Gyrase protein against the lead compound 10g and the reference drug (CFX-Ciprofloxacin). Furthermore, the drug-likeliness of the synthesized compounds was computed based on Lipinski's rule of five and ADME pharmacokinetic parameters. Thus, a chalcone-based lead 10g was identified in our study and showed promising antitubercular activity with drug-like properties. The identified lead molecule could act as a starting point to develop novel, potent antitubercular agents against the parental and drug-resistant tuberculosis strains.

Isolation, bioevaluation and RP-HPLC method development for the chemical constituents of aerial parts of Scutellaria prostrata Jacq. ex Benth

Scutellaria (Lamiaceae), commonly known as skullcaps, is one of the most popular and multi-purpose herb used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, bacterial and viral infections. Chemical investigation of methanolic extract of aerial parts of Scutellaria prostrata, a perennial herb growing as a lonely species in Kashmir Himalaya, led to the isolation of eight known constituents viz. chrysin (1), acteoside (2), martynoside (3), leucosceptoside A (4), complanatin (5), daucosterol (6), stigmasterol (7) and 1-hexacosanol (8). The isolated compounds were characterized on the basis of spectral data. A simple RP-HPLC isocratic elution method comprising of MeOH:Water (35:65) was was developed for the compounds depicting clear baseline separation with reasonable retention time and no tailing and fronting of peaks which were highly symmetric and well resolved for all analytes. was observed.. Only two compounds viz., 1 and 5 showed significant antioxidant activity at 100 µM in both DPPH and FRAP assay. All the isolated compounds exhibited dose-dependent cytotoxic effects against four different human cancer cell lines viz. pancreatic (Mia-Paca-2), lung (A-549), breast (MCF-7) and leukemia (HL-60), when tested at different concentrations (10-100 μM). Compounds 1 and 7 showed promising antitubercular activity against Mycobacterium tuberculosis (H37Rv) strain with MIC values of 25 μg/ml and 12.5 μg/ml. Based on the results obtained we can safely conclude that the developed method along with the biological screening can serve as a quality control method for standardisation of Scutellaria prostate and platform for deeper understanding of pharmacological importance of this medicinal plant.

DTP/SiO2 Assisted Synthesis of New Benzimidazole-Thiazole Conjugates Targeting Antitubercular and Antioxidant Activities

A series of new substituted benzimidazole-thiazoles (9a–l) have been designed and synthesized using 2-aminothiazole as a starting material by using molecular hybridization approach. The newly synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS analyses. The compounds (9a–l) were evaluated for their in vitro antitubercular activity against Mtb (MTCC 300) strain. Among the screened compounds 9a, 9b, 9c and 9d have displayed promising antitubercular activity with MIC 7.55, 4.60, 15.39 and 28.38 μg/mL, respectively. All the compounds were further evaluated for their DPPH radical scavenging activity. The compounds 9a, 9b and 9d were exhibited excellent radical scavenging activity. In addition to this, single crystal structure of compound 9a was also studied. Furthermore, the high potency of these molecules was supported by ADME properties prediction as well as molecular docking study to gain an insight into the binding mode and affinity toward mycobacterial InhA.

Microwave Irradiated Eco-friendly Synthesis of Pyrimidine Derivatives as Potential Antitubercular Agents

The microwave irradiation method is applied for the efficient synthesis of pyrimidine derivatives. The synthetic protocol involves Knoevenagel condensation followed by Michael addition reaction and cyclization of equimolar quantities of aromatic aldehydes, ethyl cyanoacetate and guanidine in the presence of ethanolic NaOH solution to produce corresponding pyrimidine derivatives. The reaction mixture was allowed to reflux under microwave radiation at power level-2 for 7-12 min. The microwave heating technique offers a cleaner reaction with a shorter reaction time and improved product yield as compared to conventional synthesis. The newly synthesized compounds were characterized by their FT-IR, 1H NMR and LC-MS spectral data. All the synthesized pyrimidine derivatives were evaluated in vitro for their antitubercular activity in vitro by using the luciferase reporter phage (LRP) assay method. The antimycobacterial activity was determined in terms of the percent reduction in the relative light unit (RLU). The test compounds exhibited promising antitubercular activity against Mycobacterium tuberculosis H37Rv and clinical isolates, S, H, R and E resistant M. tuberculosis in comparison with the standard drug (isoniazid).

Design, synthesis, biological screening and molecular docking studies of novel multifunctional 1,4-di (aryl/heteroaryl) substituted piperazine derivatives as potential antitubercular and antimicrobial agents

In this paper, two series of novel multifunctional 1, 4-di (aryl/heteroaryl) substituted piperazine derivatives (6a-d &7a-d) were synthesized, characterized, and evaluated for their antitubercular, antibacterial, and antifungal activities. A step-wise reduction, bromination and substitution reactions on various aldehydes resulted in alcohols (2a–d), bromides (3a–d), and titled novel compounds (6a–d &7a–d) in moderate to good yields (48–85%). The novel compounds were evaluated for their antitubercular and antimicrobial activities. Compound 7a exhibited promising antitubercular activity (MIC: 0.65 µg/mL) almost equal to the Rifampicin, while the rest of the compounds were moderately active against MTB H37Rv except 6b. Compounds 7a and 6b showed good activity against tested fungal pathogens. Compounds 7a and 7b were proven as the best bacterial agents. Molecular docking studies were in agreement with the in-vitro results. Docking analyses show that all the synthesized molecules bind to the target protein Mtb RNAP (PDB ID: 5UHC) fairly strongly. All the compounds were evaluated for their in vitro cytotoxicity effect using the MTT assay method against human cancer cell line MCF-7. The compounds demonstrated growth inhibitory effect on the cell line with significant IC50 values ranging between 8.20 and 34.45 µM. Most importantly, compound 7a displayed good binding affinity towards the tested protein with binding energy −7.30 kcal/mol and a stronger hydrogen bond distance of 2.2 Å with ASN-493 residue. Thus, the present research highlighted the potential role of novel piperazine derivatives as potential antitubercular, and antimicrobial candidates and further good research into optimization might result in the development of new antitubercular drug candidates.

Antitubercular Potential of Novel Isoxazole Encompassed 1, 2, 4- Triazoles: Design, Synthesis, Molecular Docking Study and Evaluation of Antitubercular Activity

Background: Decaprenylphosphoryl-β-D-ribose epimerase (DprE1), a flavoprotein enzyme engaged in the biosynthesis of decaprenylphosphoryl-β-D-arabinofuranose (DPA), is the only contributor of arabinose residues which is fundamental for the mycobacterium cell wall constituents. DprE1 is an interesting target for antitubercular agent and has been exploring to develop potential chemical entities as antitubercular agents. Objective: The objective of the study is the development of novel antitubercular agents targeting Mtb Decaprenylphosphoryl-β-D-ribose epimerase (DprE1). Methods: A series of isoxazole encompassed 1, 2, 4-triazoles were designed based on the antitubercular potential of triazoles and structural features of DprE1 inhibitors. Designed 1, 2, 4- triazoles were synthesized and characterized by spectral studies. The in vitro anti-TB activity of the compounds was screened against Mycobacterium tuberculosis H37Rv strain by Microplate Almar Blue Assay and in vitro cytotoxicity against normal cell lines by MTT assay. Molecular docking study was carried out on DprE1 enzyme to understand designed compounds interactions with amino acid residues at the active site. Results: Antitubercular activity data revealed that eight compounds (6d, 6e,7d, 7e, 10d, 10e, 11d and 11e) have shown promising antitubercular activity with minimum inhibitory concentration at 1.6μg/mL. Cytotoxicity data of anti-TB active compounds demonstrate good safety profile on normal cell lines. Conclusion: Eight compounds have shown promising antitubercular activity with good safety profile on normal cell lines. Molecular docking study revealed that the synthesized compounds have shown non-covalent interactions with amino acid residues of DprE1 enzyme.

Antitubercular properties of thiazolidin-4-ones - A review.

Thiazolidin-4-one scaffold has great potential for medicinal chemistry and is of interest to scientists in view of wide spectrum of biological activity. This scaffold is often used for designing of small molecules with various biological activity including antituberculosis activity. The presented review is an attempt to gather, analyze and systemize data about antitubercular properties of thiazolidine-4-ones from two last decades. Some of them have promising antitubercular activity which is significantly higher than that of the reference drugs. Among them compounds 82c, 82d and 84 that were active against M.tuberculosis H37Rv strain with MICs in the range of 0.05-0.2μg/mL and compound 108 exhibited activity with MIC=0.36μM. Compounds 115a-115c and 116a-116c were very effective against M.tuberculosis H37Ra with MIC values in the range of 0.031-0.125μg/mL. Acidomycin was showed activity against seven MDR M.tuberculosis strains with MICs in the range of 0.6-0.62μM and against two XDR M.tuberculosis strains with MICs 0.096 and 1.2μM. The structure-activity relationship (SAR) of some groups of compounds, as well as some potential molecular targets were also discussed.

Anti-HIV and Antibacterial Activities of Novel 2-(3-Substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones

In the present study, we have synthesized a series of novel 2-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones by the reaction of 3-(substituted)-2-hydrazino-quinazoline-4(3H)-ones with phthalic anhydride. The starting material 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different gram positive and gram negative strains by agar dilution method. Among the test compounds, 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-dione (QCT7) shown most potent antibacterial activity against E. coli, and S. aureus with the MIC of 3 µg/mL. The compound QCT7 exhibited the antitubercular activity with the MIC of 25 µg/mL and anti-HIV activity with the EC50 of 43.68 µM against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.

Synthesis and biological evaluation of novel indolyl-dihydropyridin-3-carboxylate, dihydro[1,2,4]triazol[1,5]pyridin-3-carboxylate and carbohydrazide derivatives

The present study anticipates the development of novel antioxidant, antimicrobial and antitubercular drugs by using the indole scaffold. Novel indole derivatives, (4a-c), (5a-c) and (6a-i) have been prepared. The structures of all these unknown compounds have been confirmed with the help of elemental analysis, IR, 1H & 13C NMR and mass spectral data. All these previously unknown synthesized compounds screened for their antioxidant, antimicrobial and antitubercular activities. Compound 5a exhibited good RSA 76.58 %, IC50 value <25 µg/mL. Compound 5a exhibited higher absorbance 0.691nm, at concentration 100 µg/mL. Compound 6a showed good metal chelating activity (64.10 %) at a concentration 100 µg/mL. Compound 6a showed potent activity against S. aureus and P. aeruginosa. Compounds 4a and 5a showed promising antitubercular activity MIC 6.25 µg/mL. Compound 6a showed excellent activity (MIC= 3.125 µg/mL) against M. tuberculosis H37Rv, than the standards pyrazinamide (MIC= 3.125) and Streptomycin (6.25 µg/mL).

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure–activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.