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1.
Eur J Med Chem ; 185: 111812, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31703818

RESUMO

Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 µM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Metaloproteases/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Humanos , Ácidos Hidroxâmicos/química , Metaloproteases/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Relação Estrutura-Atividade , Tiazolidinedionas/química
2.
J Enzyme Inhib Med Chem ; 34(1): 1730-1739, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31822127

RESUMO

A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable MtbTMPK inhibitory activity. Compounds 4b and 4i were slightly more potent than the parent compound 3. Moreover, contrary to the latter, amide analogue 4g was active against the avirulent M. tuberculosis H37Ra strain (MIC50=35 µM). This finding opens avenues for future modifications.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Timina/farmacologia , Amidas/síntese química , Amidas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Timina/síntese química , Timina/química
3.
Org Biomol Chem ; 17(43): 9524-9528, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31659363

RESUMO

Dimeric benzoboroxoles that are covalently linked by a short scaffold enhance selective anti-tubercular activity. These multimeric benzoboroxole compounds are capable of engaging the specific extracellular Mycobacterium tuberculosis glycans, do not lead to the evolution of resistance and bypass the need to cross the impermeable mycobacterial cell envelope barrier.


Assuntos
Antituberculosos/farmacologia , Ácidos Borônicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Células A549 , Antituberculosos/síntese química , Antituberculosos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Dimerização , Eritrócitos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular
4.
Chem Biodivers ; 16(12): e1900461, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557406

RESUMO

The discovery of new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a-10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1'-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis ß-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds.


Assuntos
Antibacterianos/síntese química , Dissulfetos/química , Ureia/análogos & derivados , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Animais , Antibacterianos/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Células RAW 264.7 , Relação Estrutura-Atividade , Ureia/farmacologia
5.
Eur J Med Chem ; 183: 111713, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557610

RESUMO

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host macrophage for the indefinite period. Hence, it is necessary to enhance the efficacy of the clinically existing antitubercular agents or to discover new anti antitubercular agents. Here, we report the synthesis, characterization and antimycobacterial evaluation of protein-drug conjugates. A carrier protein, Transferrin (Tf) was covalently conjugated to isoniazid (INH) utilizing hydrazone and amide linkers. The purity of the reactions was confirmed by SDS-PAGE while conjugation was confirmed by UV-visible spectrophotometry, MALDI-TOF analysis, and FTIR spectrophotometry. The in vitro antitubercular assay result showed that the inhibitory activity of the parent drug was conserved in both the conjugates. The conjugates were effective against intracellular Mtb H37Rv and were devoid of cytotoxic effect at therapeutic concentration.


Assuntos
Antituberculosos , Isoniazida , Mycobacterium tuberculosis/efeitos dos fármacos , Transferrina , Tuberculose/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/farmacologia , Estabilidade de Medicamentos , Humanos , Isoniazida/síntese química , Isoniazida/química , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Transferrina/química , Tuberculose/microbiologia
6.
Eur J Med Chem ; 181: 111578, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401536

RESUMO

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 µM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 µM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 µM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Carbamatos/síntese química , Células Hep G2 , Humanos , Isocitrato Liase/antagonistas & inibidores , Isocitrato Liase/metabolismo , Mycobacterium tuberculosis/enzimologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Salicilanilidas/síntese química , Salicilanilidas/química , Salicilanilidas/farmacologia , Tuberculose/tratamento farmacológico
7.
Eur J Med Chem ; 181: 111549, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376569

RESUMO

Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.


Assuntos
Antituberculosos/farmacologia , Benzofenantridinas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Benzofenantridinas/síntese química , Benzofenantridinas/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Estrutura-Atividade
8.
Acta Crystallogr C Struct Chem ; 75(Pt 8): 1031-1035, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31380784

RESUMO

Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one, C20H23F3N4O3S} is a promising new drug for treating drug-sensitive and drug-resistant TB that has successfully completed phase I clinical trials. We report the complete spectroscopic and structural characterization by 1H NMR, 13C NMR, HRMS, IR, and X-ray crystallography. The cyclohexyl moiety is observed to be nearly perpendicular to the core formed by the 1,3-benzothiazin-4-one and piperazine groups. The central piperazine ring adopts a slightly distorted chair conformation caused by sp2-hybridization of the nitro N atom, which donates into the electron-deficient 1,3-benzothiazin-4-one group.


Assuntos
Antituberculosos/química , Piperazinas/química , Tiazinas/química , Antituberculosos/síntese química , Cristalografia por Raios X , Farmacorresistência Bacteriana , Ligações de Hidrogênio , Conformação Molecular , Piperazinas/síntese química , Tiazinas/síntese química , Tuberculose Pulmonar/tratamento farmacológico
9.
Eur J Med Chem ; 180: 648-655, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31352245

RESUMO

Herein, synthesis and biological evaluation of fourteen moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible (MTB H37Rv), rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains were reported, and cytotoxicity towards VERO cells as well as inhibitory activity against MTB DNA gyrase were also discussed in this paper. The structure-activity relationship and structure-cytotoxicity relationship demonstrated that substituents on the C-3 and C-5/C-7 positions of isatin framework were closely related with the anti-mycobacterial activity and cytotoxicity. The most active hybrids 8h and 8l (MIC: 0.12-0.5 µg/mL) showed excellent activity which was no inferior to the parent moxifloxacin against the tested drug-susceptible, rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains, demonstrating their potential application as novel anti-tubercular candidates.


Assuntos
Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Isatina/farmacologia , Moxifloxacina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Triazóis/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Isatina/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Moxifloxacina/química , Relação Estrutura-Atividade , Triazóis/química , Células Vero
10.
Arch Pharm (Weinheim) ; 352(9): e1900068, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339194

RESUMO

5-Substituted-6-acetyl-2-amino-7-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte-derived macrophage (THP-1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95-125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow-growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l, showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole-cell mycobacterial drug-efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.


Assuntos
Antituberculosos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/síntese química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacteriaceae/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Células RAW 264.7 , Staphylococcus aureus , Relação Estrutura-Atividade , Células THP-1
11.
Eur J Med Chem ; 180: 562-612, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344615

RESUMO

Heterocycles occupy a salient place in chemistry due to their wide range of activity in the fields of drug design, photochemistry, agrochemicals, dyes, and so on. Amongst all, indole scaffold is considered as one of the most promising heterocycles found in natural and synthetic sources and has been shown to possess various biological activity, including anti-inflammatory, anti-HIV, antitubercular, antimalarial, anticonvulsant, antidiabetic, antihypertensive, analgesics, antidepressant, anticancer, antioxidant, antifungal, and antimicrobial, etc. All the reported indole molecules bind to multiple receptors with high affinity, thus expedite the research on the development of novel biologically active compounds through the various approach. In this review, we aimed to highlight synthetic and medicinal perspective on the development of indole-based analogs. In addition, structural activity relationship (SAR) study to correlate for their biological activity also discussed.


Assuntos
Indóis/síntese química , Indóis/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 178: 39-47, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176094

RESUMO

Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro. 8 compounds show activity as potential serine/threonine protein kinase (STPK) inhibitors in M. smegmatis aphVIII+ test-system, which is characteristic for this class. 3 compounds out of 5 most active STPK inhibitors have a prominent minimal inhibitory concentration on M. tuberculosis H37Rv of 1 µg/ml. We were able to obtain M. smegmatis mc2 155 mutants resistant to 4 compounds and show that they do not have cross resistance with other drugs, but have a common mechanism of resistance among these 4 imidazo[1,2-b][1,2,4,5]tetrazines. Compound 3h seems the most promising, combining a predicted STPK inhibitor activity, the lowest MIC on M. tuberculosis and a low frequency of drug resistant mutants' emergence.


Assuntos
Antituberculosos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Imidazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Eritromicina/farmacologia , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/síntese química , Imidazóis/química , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Ofloxacino/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rifampina/farmacologia
13.
Eur J Med Chem ; 178: 315-328, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195172

RESUMO

The dormant and resistant form of Mycobacterium tuberculosis presents a challenge in developing new anti-tubercular drugs. Herein, we report the synthesis and evaluation of trisubstituted thiazoles as antituberculosis agents. The SAR study has identified a requirement of hydrophobic substituent at C2, ester functionality at C4, and various groups with hydrogen bond acceptor character at C5 of thiazole scaffold. This has led to the identification of 13h and 13p as lead compounds. These compounds inhibited the dormant Mycobacterium tuberculosis H37Ra strain and M. tuberculosis H37Rv selectively. Importantly, 13h and 13p were non-toxic to CHO cells. The 13p showed activity against multidrug-resistant tuberculosis isolates.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
14.
Eur J Med Chem ; 179: 208-217, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254922

RESUMO

IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IR > 90% at 10 µM). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078 µM), and had lower hERG binding affinity (IR < 50% at 10 µM). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Descoberta de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 176: 492-512, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132480

RESUMO

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L2-, H2L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO3 (3), [Fe(L)(amphen)]PF6 (3a), [Fe(L)(Clphen)]PF6 (4), [Fe(L)(epoxyphen)]PF6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1H and 13C NMR and fluorescence spectroscopies. [Fe(phen)Cl3] and [Fe(amphen)Cl3] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ferro/química , Fenantrolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , DNA/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Desenho de Drogas , Estabilidade de Medicamentos , Humanos , Ligantes , Mycobacterium tuberculosis/efeitos dos fármacos , Fenantrolinas/síntese química , Fenantrolinas/química , Fenantrolinas/toxicidade , Estudos Prospectivos , Espécies Reativas de Oxigênio/metabolismo
17.
Eur J Med Chem ; 177: 12-31, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129451

RESUMO

Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'-isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carbohydrazide analogs (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1H NMR, 13C NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and anti-mycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (InhA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Pirimidinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Coenzima A Ligases/química , Coenzima A Ligases/metabolismo , Isoniazida/metabolismo , Isoniazida/farmacocinética , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética
18.
Eur J Med Chem ; 174: 309-329, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31055147

RESUMO

Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Isoquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/química , Isoquinolinas/síntese química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade
19.
Arch Pharm (Weinheim) ; 352(6): e1800358, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066103

RESUMO

Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)-piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 µg/ml). Compound R7 was found to be moderately active with an IC50 of 2.1 ± 0.04 µM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Antituberculosos/farmacologia , Desenho de Drogas , Iminas/farmacologia , Tuberculose/tratamento farmacológico , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antituberculosos/síntese química , Antituberculosos/química , Simulação por Computador , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Iminas/síntese química , Iminas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia
20.
Org Biomol Chem ; 17(22): 5428-5459, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31111850

RESUMO

Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.


Assuntos
Antituberculosos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos
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