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[Display omitted] • A library of triazole–quinazolinone molecular hybrids have been synthesized using click reaction. • Six derivatives emerged as potent agents against plasmodium species P. falciparum. • Three derivatives have displayed potent antitubercular activity against M. tuberculosis (MTB) H37Rv strain. In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole–quinazolinone hybrids. The in vitro screening of the triazole–quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c , 6d , 6f , 6g , 6j & 6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c , 6d and 6l were found to be the most active molecules with a MIC values of 19.57–40.68 μM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a , 6g , and 6k exhibited highest binding affinity of −10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole–quinazolinone hybrids may be considered hit molecules for further optimization studies. [ABSTRACT FROM AUTHOR]

[Display omitted] To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against Mtb, no cytotoxicity against both HEK293T and HepG2 mammalian cell lines, and had good in vivo mouse plasma exposure and lung concentration with a 20 mg/kg oral dose, which supports advanced development as a new chemical entity for TB treatment. [ABSTRACT FROM AUTHOR]

Among the series of 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines synthesized, compound 7l inhibited influenza virus with good selectivity index (IC 50 = 19.5 μg/mL; SI = 15) and compound 7a (MIC: 3.12 μg/mL) emerged as potent inhibitor of M. tuberculosis. This study describes synthesis and evaluation of novel 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines 7a-o as dual inhibitors of Mycobacterium tuberculosis and influenza virus. Huisgen's [3+2] dipolar cycloaddition of 6-(azidomethyl)-5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline 5 with various alkynes 6a-o using sodium ascorbate and copper sulphate gave new dihydroquinoline-1,2,3-triazoles 7a-o in good to excellent yields. The new compounds were evaluated for in vitro antimycobacterial against M. tuberculosis H37Rv (Mtb) and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). Among the fifteen new analogs, compounds 7a (MIC: 3.12 µg/mL), 7j and 7k (MIC: 6.25 µg/mL) were identified as potent antitubercular agents. The virus-inhibiting activity of all the fifteen compounds was found to be moderate, and among them the compound 7l , bearing thiophene moiety appeared the most active with good selectivity index (IC 50 = 19.5 µg/mL; SI = 15). The results presented here will help developing newer dual inhibitors of tuberculosis and influenza virus. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of novel substituted 1,2,3-triazolyldihydroquinolines 6a–o was designed and synthesized from 2-acetylthiophene in five-step reaction sequence involving modified Boltzmann-Rahtz reaction of β-Enaminone; Vilsmeier-Haack chloroformylation using DMF/POCl 3 ; Ohira-Bestmann homologation of aldehyde to alkyne as key steps. The reaction of alkyne 4 with various aryl azides in the presence of copper sulfate and sodium ascorbate resulted desired new 1,2,3-triazolyldihydroquinolines 6a–o in excellent yields. In vitro screening of new compounds for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (Mtb), resulted in three derivatives 6a (MIC:1.56 µg/mL) and 6d , 6l (MIC:3.12 µg/mL) as promising antitubercular agents with lower cytotoxicity profiles. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The optimization campaign for a nitrofuran antitubercular hit (N -benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019–0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC 50 = 40–>120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC 50 > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty four novel bioactive compounds consist pyrrolopyrimidine-triazole were synthesized. • Compounds 4r and 4q showed excellent activity against Mycobacterium tuberculosis H37Rv. • SAR revealed the effect of different substituents on the triazole ring. Abstract A series of novel 1 H -pyrrolo[2,3- d ]pyrimidine-1,2,3-triazole derivatives have been synthesized in good to excellent yields. Through the copper-catalyzed azide-alkyne cycloaddition via reaction of 7-(prop-2-ynyl)-7 H -pyrrolo[2,3- d ]pyrimidine and aryl, heteroaryl and alkyl azides in the presence of CuSO 4 ·5H 2 O and sodium ascorbate. These compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Most of these pyrrolopyrimidine-triazole hybrids exhibited good anti tubercular activity. The antimycobacterial assay results showed that the minimum inhibitory concentration of compounds 4q and 4r were 0.78 µg/mL. The molecular docking results also had shown highest Moldock score for same compounds. These novel compounds exhibited good inhibition activities and further structure-activity studies of the derivatives had shown promising features to use in antitubercular therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New quinoline scaffolds show improved chemical stability; handle for further optimization. • Subsequent SAR identified quinoline-2-acrboxamides with potent antitubercular activity. • Hit-to-lead efforts yielded a potent FadD32 inhibitor with notable in vivo efficacy in mouse model of TB infection. Abstract Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection. [ABSTRACT FROM AUTHOR]

We report herein the design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide derivatives containing fused ring moieties. Results reveal that many of the target compounds have considerable in vitro antitubercular activity. Especially, N -((2-(4-fluorophenyl)/ N -((2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquilin-6-yl)methyl)-3,5-dinitrobenzamides 18a and 20e exhibit potent MIC values of 0.056–0.078 μg/mL against both drug-sensitive Mycobacterium tuberculosis (MTB) H37Rv strain and two clinically isolated multidrug-resistant MTB (MDR-MTB) strains, opening a new direction for further SAR studies. [ABSTRACT FROM AUTHOR]

A series of small molecules with novel pyrrolo[1,2- a ]quinoxaline-based scaffold was designed via molecular hybridization of privileged agents active against Mycobacterium tuberculosis . Twenty-three compounds were synthesized and investigated for their antitubercular activities in vitro where ten compounds showed appreciable activities and moderate cytotoxicity. Compound 12g with MIC values of 5 μg/ml as a representative may possess better oral bioavailability and indicated high permeability by the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB). Further, the determination of enzyme inhibition and molecular docking study indicated that InhA may be the biological target of the active compounds. The results suggest the pyrrolo[1,2- a ]quinoxaline hybrids as potential antitubercular leads for the development of new antitubercular agents. [ABSTRACT FROM AUTHOR]

Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis ( Mtb ). Inosine 5′-monophosphate dehydrogenase (IMPDH), guaB2 , of Mtb , required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive Mtb H37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb- GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb , followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb , and activity on human IMPDH2 isoform. One of the hits, 13 , a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb -GuaB2 enzyme. The hit, 13 , is a promising molecule with potential for further development as an antitubercular agent. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD + ) synthetase catalyzes the last step in NAD + biosynthesis. Depletion of NAD + is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD + synthetase (NadE) from Mtb, we expect to eliminate NAD + production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure–activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC 50 = 1000 µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f , the most potent compound of the series with an IC 50 value of 90 µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19–100 µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target. [ABSTRACT FROM AUTHOR]

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β- d -ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions. [ABSTRACT FROM AUTHOR]

An efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-N-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. All synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) and cytotoxicity activity against normal VERO cell lines. The synthesized compounds exhibited minimum inhibitory concentration (MIC) ranging from 0.78 to 25 μM. Among the tested compounds 4c , 4o , 4r , and 4u exhibited promising inhibitory activity (MIC = 3.12 μM). Compounds 4h and 4i stand out, showing MIC values of 0.78 and 1.56 μM respectively. Both compounds were further screened for their Mycobacterium tuberculosis DNA gyrase inhibitory assay which suggested that these compounds have a great potential for further optimization and development as antitubercular agents. [ABSTRACT FROM AUTHOR]

A series of quinoline incorporated monocarbonyl curcumin analogues was efficiently synthesized using [HDBU][HSO 4 ] as catalyst via Knoevenagel type condensation and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG in dormant state. The analogues 3e , 3h , 4a and 4e exhibited very good antitubercular activity. The antiproliferative activity of the analogues against MCF-7, A549 and HCT-116 cell lines was evaluated using modified MTT assay and these compounds were found to be non-cytotoxic. Molecular docking study has been carried out against M. tuberculosis pantothenate synthetase (MTB PS) enzyme in an effort to enhance the understanding of their action as antitubercular agents. The potency, low cytotoxicity and selectivity of these analogues support them as valid leads for further optimization. [ABSTRACT FROM AUTHOR]

The enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel antitubercular agents. A series of gallic acid formazans, were computationally designed and docked into the active site of InhA to understand their binding mode and potential to inhibit InhA. Nine compounds from the designed series were identified as potential InhA inhibitors, on the basis of good Glide score . These compounds were synthesized in the laboratory and evaluated for in vitro antitubercular activity against drug-sensitive and multi-drug resistant strains of MTB. Out of nine compounds, three compounds exhibited the most promising MIC of <2 μM against the sensitive strain of MTB, H37Rv. The compounds were evaluated against five resistant strains of MTB. Most of the compounds exhibited activity superior to the standard, linezolid, against all these resistant strains. The mechanism of action of these compounds was concluded to be InhA inhibition, through InhA enzyme inhibition study. Insignificant cytotoxicity of these compounds was observed on RAW 264.7 cell line. Inactivity of all these compounds against gram positive and gram negative bacteria indicated their specificity against MTB. The compounds were further analyzed for ADME properties and showed potential as good oral drug candidates. The results clearly identified some novel, selective and specific InhA inhibitors against sensitive and resistant strains of MTB. [ABSTRACT FROM AUTHOR]

A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6µlg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25µg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6µg/mL) followed by H13 (6.25µg/mL) and H17 (12.5µg/mL), H19 (3.125µg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and b-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH. [ABSTRACT FROM AUTHOR]

A series of biheterocyclic (1H-indole, benzofuran, pyrazolo[1,5- a ]pyrimidine, pyrazolo[1,5- a ]pyrimidin-5(4H)-one, imidazo[2,1- b ]thiazole and pyrazolo[5,1- b ]thiazole) derivatives were synthesized and evaluated for their anti-tubercular activities. The imidazo[2,1- b ]thiazoles 9a – c and pyrazolo[5,1 -b ]thiazoles 10a – c exhibited promising anti-tubercular activity in varying degrees. Especially, the 2,6-dimethylpyrazolo[5,1- b ]thiazole 10a exhibited strong suppressing function against H37Ra strain with MIC value of 0.03 μg/mL. Compound 10a also displayed good pharmacokinetic profiles with oral bioavailability ( F ) of 41.7% and a half-life of 13.4 h. Furthermore, 10a significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential for development of anti-tubercular drugs. [ABSTRACT FROM AUTHOR]

2-Propargylthiobenzimidazole 1 , 4-bromomethyl coumarins/1-aza-coumarins 2 / 3 and sodium azide have been reacted in one pot under Click chemistry conditions to give exclusively 1,4-disubstituted triazoles 5a – n . Anti-tubercular assays against M. tuberculosis (H 37 Rv) coupled with in silico molecular docking studies indicated that dimethyl substituents 5c and 5d showed promising activity with higher C-score values. [ABSTRACT FROM AUTHOR]

A series of benzosuberone bearing 1,2,3-triazoles were rationally designed and alkyl/aryl groups appended on 1,2,3-triazole derivatives 5a – o were synthesized using click chemistry and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Compounds 5h (MIC: 3.125 μg/mL) and 5l , 5m , 5o (MIC: 6.25 μg/mL) exhibited promising hits. This is the first Letter on the synthesis and in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv of benzosuberone alkyl/aryl groups appended on 1,2,3-triazole derivatives. [ABSTRACT FROM AUTHOR]

The emergence of antibiotic resistant pathogens is an ongoing main problem in the therapy of bacterial infections. In order to develop promising antitubercular and antibacterial lead compounds, we designed and synthesized a new series of derivatives of 2-aminothiazole conjugated nitrofuran with activities against both Mycobacterium tuberculosis and Staphylococcus aureus . Eight compounds 12e , 12k , 12l , 12m , 18a , 18d , 18e , and 18j emerged as promising antitubercular agents. Structure–activity relationships (SARs) were discussed and showed that the derivatives substituted at the position-3 of benzene of 5-nitro- N -(4-phenylthiazol-2-yl)furan-2-carboxamide exhibited superior potency. The most potent compound 18e , substituted with benzamide at this position, displayed minimum inhibitory concentrations (MICs) of 0.27 μg/mL against Mtb H37Ra and 1.36 μg/mL against S. aureus . Furthermore, compound 18e had no obvious cytotoxicity to normal Vero cells (IC 50 = 50.2 μM). The results suggest that the novel scaffolds of aminothiazole conjugated nitrofuran would be a promising class of potent antitubercular and antimicrobial agents. [ABSTRACT FROM AUTHOR]

A series of novel dibenzofuran tethered thiazolyl-1,2,3-triazolyl acetamides, designed by assembling antitubercular pharmacophoric fragments, dibenzofuran, 2-aminothiazole and substituted triazoles in one molecular architecture, were evaluated against Mycobacterium tuberculosis . The new analogues 6a – p accomplished in four step synthetic sequence utilizing click chemistry in the penultimate step, was fully characterized by their NMR and mass spectral data. Among the compounds 6a – p screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, three compounds 6j (MIC: 1.56 μg/mL); 6a and 6p (MIC: 3.13 μg/mL) was found to be most active and exhibited lower cytotoxicity. Among these three, 6j could be a candidate to consider as a drug like hit analogue for further development. [ABSTRACT FROM AUTHOR]

A series of thirty eight novel 3-(4-((substituted-1 H -1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[ d ]isoxazole and 1-(4-(benzo[ d ]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1 H -indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two ‘wild’ strains Spec. 210 and Spec. 192 . The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200 μM. Among the tested compounds, 7i , 7y and 7z exhibited moderate activity (MIC = 24.03–29.19 μM) and 7j exhibited very good anti-tubercular activity (MIC = 6.16 μM). Furthermore, 7i , 7j , 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor. [ABSTRACT FROM AUTHOR]

Parallel solid phase synthesis offers a unique opportunity for the synthesis and screening of large numbers of compounds and significantly enhances the prospect of finding new leads. We report the synthesis and antitubercular activity of chiral 1,2,4-trisubstituted piperazines derived from resin bound acylated dipeptides against Mycobacterium tuberculosis strain H37Rv. [ABSTRACT FROM AUTHOR]

In search of new active molecules against Mycobacterium tuberculosis ( MTB ) H37Ra and Mycobacterium bovis BCG , a small focused library of rhodanine incorporated tetrazoloquinoline has been efficiently synthesized by using [HDBU][HSO 4 ] acidic ionic liquid. The compound 3c found to be promising inhibitor of MTB H37Ra and M. bovis BCG characterized by lower MIC values 4.5 and 2.0 μg/mL, respectively. The active compounds were further tested for cytotoxicity against HeLa, THP-1, A549 and PANC-1 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated. Again, the synthesized compounds were found to have potential antifungal activity. Furthermore, to rationalize the observed biological activity data, the molecular docking study also been carried out against a potential target Zmp1 enzyme of MTB H37Ra , which revealed a significant correlation between the binding score and biological activity for these compounds. The results of in vitro and in silico study suggest that these compounds possess ideal structural requirement for the further development of novel therapeutic agents. [ABSTRACT FROM AUTHOR]

A high-throughput screening effort on 45,000 compounds resulted in the discovery of a disubstituted oxazole as a new structural class inhibitor of Mycobacterium tuberculosis (Mtb). In order to improve the activity and investigate the SAR of this scaffold, a series of disubstituted azole analogues have been designed and synthesized. The newly synthesized compounds 1a – y were evaluated for their in vitro anti-TB activity versus replicating, multi- and extensive drug resistant Mtb strains. All the compounds, except 1o , 1p and 1q , showed potent anti-TB activity with MIC of 1–64 mg/L. The test of broad spectrum panel revealed that this series are specific to Mtb. The cytotoxicity assessment indicated that the compounds were not cytotoxic against HEK 293 cells. The compounds could have a novel mechanism to anti-Mtb as they can inhibit drug sensitive and drug resistant Mtb. [ABSTRACT FROM AUTHOR]

A new series of triazole–imidazo[2,1- b ][1,3,4]thiadiazole hybrids ( 6a – s , 7a ) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were characterised using spectral methods and one of the target compounds ( 6c ) was analysed by the single crystal XRD study. The derivatives were screened for their antimycobacterial activity against Mycobacterium tuberculosis H 37 Rv strain. Two compounds, 6f and 6n , demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of 3.125 μg/mL. The presence of chloro substituent on the imidazo[2,1- b ][1,3,4]thiadiazole ring and ethyl, benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general cellular toxicity of these compounds. [ABSTRACT FROM AUTHOR]

Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[indene-1,4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2,4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1,4′-piperidin]-2(1 H )-one (abbr. spiroindolones). Spiroindenes showed ⩾4 log 10 kill (at 2–12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives. [ABSTRACT FROM AUTHOR]

[Display omitted] Tuberculosis (TB) is one of the deadliest infectious diseases worldwide and its current treatments have been complicated with the emergence of multi-drug resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. Therefore, the discovery of new antitubercular agents is in need to overcome this problem. In our efforts to discover novel candidates for the treatment of tuberculosis, we describe in this work in vitro activity against M. smegmatis for a series of aminated benzo-fused heterocycles, particularly, dibenzothiophene to explore the structure–activity relationship of 2-aminodibenzothiophene 3aa. From these studies, three compounds 5-aminobenzothiophene 3ia, 6-aminobenzothiophene 3ma (MIC: 0.78 µg/mL) and 5-aminobenzofuran 3ja (MIC: 1.56 µg/mL) were identified as potent inhibitors of M. smegmatis with low cytotoxicity. These results suggested the significance of these compounds 3ia, 3ja and 3ma for the future development of candidate agents to treat tuberculosis. [ABSTRACT FROM AUTHOR]

A series of imidazo[1,2- a ]indeno[1,2- e ]pyrazin-4-ones that potently inhibit M. tuberculosis glutamine synthetase (GlnA1) has been identified by high throughput screening. Exploration of this series was performed owing to a short chemistry program. Despite possibly nanomolar inhibitions, none of these compounds was active on whole cell Mtb , suggesting that GlnA1 may not be a suitable target to find new anti-tubercular drugs. [ABSTRACT FROM AUTHOR]

A series of novel carbazole tethered pyrrole derivatives were designed by coupling core fragments of antitubercular agents, carbazole and substituted pyrrole in single molecular architecture. The synthesis of new analogues was achieved by FeCl 3 mediated one pot three component condensation of 2-nitrovinylcarbazoles with aryl or alkyl amines and dimethylacetylene dicarboxylate (DMAD). All the new analogues 5a – l and 6a – l were fully characterized by their NMR and mass spectral data. Among the twenty four new compounds screened for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv, dimethyl 1-(4-fluorophenyl)-4-(9-methyl-9 H -carbazol-3-yl)-1 H -pyrrole-2,3-dicarboxylate ( 5b ) was found to be most active with MIC 3.13 μg/mL and has shown low cytotoxicity. [ABSTRACT FROM AUTHOR]

A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis ( Mtb ) in an attempt to find an alternative scaffold to the imidazo[1,2- a ]pyridine and imidazo[1,2- a ]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb . The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2- b ]pyridazine-3-carboxamide ( 7 ), a 2,6-dimethyl-1 H -indole-3-carboxamide ( 8 ), a 6-methyl-1 H -indazole-3-carboxamide ( 9 ), a 7-methyl-[1,2,4]triazolo[4,3- a ]pyridine-3-carboxamide ( 10 ), and a 5,7-dimethyl-[1,2,4]triazolo[1,5- a ]pyrimidine-2-carboxamide ( 11 ). Additionally, imidazo[1,2- a ]pyridines isomers ( 2 and 12 ) and a homologous imidazo[1,2- a ]pyrimidine isomer ( 6 ) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H 37 Rv Mtb (MIC’s of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus , Escherichia coli and Candida albicans . Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM). [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 1,2,3-triazole-adamantylacetamide hybrids 5a–u, designed by combining bioactive fragments from antitubercular I-A09 and substituted adamantyl urea, were synthesized using copper catalyzed click chemistry. N-(1-Adamantyl)-2-azido acetamide 3 prepared from 1-adamantylamine was reacted with a series of alkyl/aryl acetylenes in the presence of copper sulfate and sodium ascorbate to give new analogues 5a–u in very good yields. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted N-(1-adamantan-1-yl)-2-(4-(phenanthren-2-yl)-1H-1,2,3-triazol-1-yl)acetamide (5t) as most promising lead MIC: 3.12μg/mL) with selectivity index >15. [Copyright &y& Elsevier]

Abstract: Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4μg/mL, representing a significant improvement in antitubercular potency in this class of compounds. [Copyright &y& Elsevier]

Abstract: Molecular hybridization is an emerging structural modification tool to design molecules with better pharmacophoric properties. A series of novel 2-(trifluoromethyl)phenothiazine-1,2,3-triazoles 5a–v designed by hybridizing two antitubercular drugs trifluoperazine and I-A09 in a single molecular architecture, were synthesized in very good yields using click chemistry. Among the all ‘22’ compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Mtb), three analogs 5c, 5l and 5o were found to be most potent (MIC: 6.25μg/mL) antitubercular agents with good selectivity index. [Copyright &y& Elsevier]

Abstract: A series of novel arylquinoline derivatives was designed retaining significant pharmacophoric features and three dimensional geometry of bedaquiline. In silico ADME study was performed to assess drug likeness and toxicity profiles of the designed molecules. The compounds were evaluated for activity against Mycobacterium tuberculosis H37Rv using Resazurin Microtitre Assay (REMA) plate method and cytotoxicity in VERO C1008 cell line. Several of the synthesized compounds exhibited good antituberculosis activity and selectivity, especially compounds, 12i (MIC: 5.18μM and MIC/CC50: 152.86) and 12l (MIC: 5.59μM and MIC/CC50: 160.57). The study opens up a new platform for the development of arylquinoline based drugs for treating tuberculosis. [Copyright &y& Elsevier]

Abstract: In an effort to develop new and potent agents for therapy against tuberculosis, a high-throughput screen was performed against Mycobacterium tuberculosis strain H37Rv. Two 6-aryl-5,7-dimethyl-4-phenylcoumarin compounds 1a and 1b were found with modest activity. A series of coumarin derivatives were synthesized to improve potency and to investigate the structure–activity relationship of the series. Among them, compounds 1o and 2d showed improved activity with IC90 of 2μM and 0.5μM, respectively. Further optimization provided compound 3b with better physiochemical properties with IC90 0.4μM which had activity in a mouse model of infection. The role of the conformation of the 4- and 6-aryl substituents is also described. [Copyright &y& Elsevier]

Abstract: Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H benzo[g]indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient methodology. The synthesized compounds (4–23) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 6a, 6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC values 50, 100, 50, 25 and 100μM concentration. In vitro cytotoxicity data using THP-1 cells indicated that most active compound 19a is safe as its MIC value is much lower than the cytotoxic value. [Copyright &y& Elsevier]

Abstract: N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. [Copyright &y& Elsevier]

Abstract: A series of 21 new amino alcohol fused spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC=3.13μg/mL. [Copyright &y& Elsevier]

Abstract: Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5μg-mL−1. In vitro cytotoxicity of compounds 16, 24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 times selective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective. [Copyright &y& Elsevier]

Abstract: A small series of C-cinnamoyl glycoside containing the phenol moiety was tested for the inhibition of the three Mycobacterium tuberculosis β-carbonic anhydrases (CAs, EC 4.2.1.1) with activities in the low micromolar range detected. The compounds were also tested for the inhibition of growth of M. tuberculosis H37Rv strain, leading to the identification of (E)-1-(2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl)-4-(3-hydroxyphenyl)but-3-en-2-one (1) as the first carbonic anhydrase inhibitor with anti-tubercular activity. [Copyright &y& Elsevier]

Abstract: One pot synthesis of 3-Aracylphthalide was accomplished in good yield by reacting 2-carboxy benzaldehyde with various aromatic methyl ketones in presence of methane sulphonic acid. Various phthalides thus obtained were characterized with spectral techniques. These phthalides were subjected to in vitro antitubercular screening against Mycobacterium tuberculosis H37Ra (MTB) by using XRMA protocol. Among the phthalides screened, four exhibited half maximal inhibitory concentration (IC50) in the range of 0.81–1.24μg/ml thereby providing potential lead compounds for future drug discovery studies. [Copyright &y& Elsevier]

Abstract: Based on bioisosteric similarities with isoniazid, a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives has been designed. The target compounds have been synthesized by multicomponent reaction which involves one-pot organic reactions using ethylcyanoacetate, urea/thiourea and arylaldehydes in presence of ethanolic K2CO3. Two methodologies, conventional and microwave-assisted, have been adopted for the synthesis. The later strategy gave high yields in less than 10min as compared to long hours using the former approach. Molecular docking of the target compounds into the enzyme Mycobacterium tuberculosis enoyl reductase (InhA) revealed important structural information on the plausible binding interactions. Major binding interactions were found to be of dispersion type (residues Tyr158, Ile215, Met103 and Met199) and a hydrogen bond with Tyr158. Binding poses of the all the compounds were energetically favorable and showed good interactions with the active site residues. Few selected compounds were also evaluated for antitubercular activity in vitro against drug-sensitive M. tuberculosis H37Rv strain and clinically isolated S, H, R and E resistant M. tuberculosis by luciferase reporter phage (LRP) assay method. Some compounds displayed promising antimycobacterial activity comparable or less than the standard drugs isoniazid and rifampicin. [Copyright &y& Elsevier]

Abstract: New derivatives of steviol 1, the aglycone of the glycosides of Stevia rebaudiana, including a novel class of semisynthetic diterpenoids, namely macrocyclic ent-kauranes were synthesized. These compounds possess antituberculosis activity inhibiting the in vitro growth of Mycobacterium Tuberculosis (H37RV strain) with MIC 5–20μg/ml that is close to MIC 1μg/ml demonstrated by antituberculosis drug isoniazid in control experiment. For the first time it was found that the change of ent-kaurane geometry (as in steviol 1) of tetracyclic diterpenoid skeleton to ent-beyerane one (as in isosteviol 2) influences on antituberculosis activity. [Copyright &y& Elsevier]

Abstract: Econazole has been known to be active against Mycobacterium tuberculosis. We have designed and synthesized 1H-1,2,3-triazoles derived from econazole as antitubercular agents. The majority of triazole derivatives have been prepared by microwave-assisted click chemistry. It turned out that all of the prepared triazoles had no antifungal activities. However, most of the hydroxy-triazoles (6a and 10) apparently turned out to have antitubercular activities. Overall, hydroxy-triazoles 10 were more active than their corresponding ether-triazoles 11. While the MIC value of hydroxy-triazole 10d was as good as econazole (16μg/mL), the MIC value of 10a was two-fold more active than econazole, suggesting that this 1H-1,2,3-triazole scaffold (3) could be further optimized to develop Mtb specific agents. [Copyright &y& Elsevier]

Abstract: TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N′-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H37Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H37Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25μM against replicating Mtb, MIC=8.0μM against non-replicating Mtb and IC50 =32μM in the VERO cellular toxicity assay. [Copyright &y& Elsevier]

Abstract: As a part of our research to develop novel antitubercular and antimicrobial agents, a series of 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesised. These compounds were tested for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system, antifungal activity against a pathogenic strain of fungi and antibacterial activity against gram-positive and gram-negative organisms. Among them tested, many compounds showed good to excellent antimicrobial and antitubercular activity. The results suggest that hydrazones, 2-azetidinones and 4-thiazolidinones bearing a core pyrazole scaffold would be potent antimicrobial and antitubercular agents. [Copyright &y& Elsevier]

Abstract: Currently used anti-tubercular drugs target actively growing Mycobacterium tuberculosis (Mtb) but there are no current therapies targeting persistent mycobacteria. Isocitrate lyase (ICL) is an important enzyme of the glyoxylate shunt pathway used by Mtb for sustaining intracellular infection in inflammatory macrophages under conditions of stress such as nutrient depletion and anaerobic metabolism. Since the humans do not possess this enzyme it constitutes an attractive target for selective drug design. Present work describes synthesis and structural characterization of pyruvate–isoniazid conjugates and their copper complexes with potent anti-tubercular activities against M. tuberculosis H37Rv. [Copyright &y& Elsevier]

Abstract: Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12μM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10mg/kg body weight) in male Wistar rats viz. t ½, K el, mean plasma clearance and mean volume of distribution were found to be 1.14±0.20h, 0.62±0.10h−1, 22.48±0.16mL/kg/min and 1.99±0.49L, respectively. The systemic absorption was slow after oral administration (50mg/kg body weight). The peak plasma concentration was found to be 1.31±0.06μg/mL attained in 3h. The bioavailability was found to be 16.7%. [Copyright &y& Elsevier]

Abstract: The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12–1.56μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents. [Copyright &y& Elsevier]