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1.
Mol Divers ; 2024 May 26.
Article in English | MEDLINE | ID: mdl-38796797

ABSTRACT

Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R2 and Q2 values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

2.
Bioorg Med Chem Lett ; 30(2): 126846, 2020 01 15.
Article in English | MEDLINE | ID: mdl-31839540

ABSTRACT

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


Subject(s)
Antitubercular Agents/therapeutic use , Pyrazinamide/chemical synthesis , Triazoles/chemical synthesis , Antitubercular Agents/pharmacology , Humans , Molecular Docking Simulation , Molecular Structure , Pyrazinamide/chemistry , Structure-Activity Relationship , Triazoles/chemistry
3.
Bioorg Chem ; 92: 103281, 2019 11.
Article in English | MEDLINE | ID: mdl-31561106

ABSTRACT

Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases.


Subject(s)
Drug Design , Histone Deacetylase Inhibitors/pharmacology , Indoles/pharmacology , Molecular Docking Simulation , Sirtuin 1/antagonists & inhibitors , Sirtuin 2/antagonists & inhibitors , Dose-Response Relationship, Drug , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Sirtuin 1/metabolism , Sirtuin 2/metabolism , Structure-Activity Relationship , Surface Plasmon Resonance
4.
Eur J Med Chem ; 168: 263-282, 2019 Apr 15.
Article in English | MEDLINE | ID: mdl-30822714

ABSTRACT

The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 µg/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads.


Subject(s)
Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Phenothiazines/pharmacology , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Triazoles/pharmacology , Adsorption , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Design , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Phenothiazines/chemistry , Phenothiazines/metabolism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/metabolism , Vero Cells
5.
Bioorg Med Chem Lett ; 25(23): 5540-5, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26520663

ABSTRACT

With the aim of developing promising antitubercular and antibacterial leads, we have designed and synthesized a new series of isonicotinohydrazide based pyrazole derivatives (5a-r). All new derivatives (4a-b and 5a-r) were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) strain. Four compounds 5j, 5k, 5l and 4b emerged as promising antitubercular agents with MIC of ⩽4.9 µM which is much lower than the MIC of the first line antitubercular drug, ethambutol. The 3-chlorophenyl substituent at position-3 of the pyrazole ring enhanced the antiTB activity of the molecules. Three derivatives 5b, 5k and 4b exhibited promising antibacterial activity against the tested bacterial strains. The active molecules were nontoxic to normal Vero cells and showed high selectivity index (>160). The structure and antitubercular activity relationship was further supported by in silico molecular docking study of the active compounds against enoyl acyl carrier protein reductase (InhA) enzyme of M. tuberculosis.


Subject(s)
Bacteria/drug effects , Drug Design , Isoniazid/chemistry , Mycobacterium tuberculosis/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Binding Sites , Inhibitory Concentration 50 , Isoniazid/chemical synthesis , Isoniazid/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Pyrazoles/chemistry
6.
Eur J Med Chem ; 106: 75-84, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26520841

ABSTRACT

A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5 g and 5 n were emerged as the most active compounds of the series with MIC of 0.8 µg/mL (∼ 1.9 µM). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 µg/mL), and compounds 5j, 5k and 5o (MIC = 3.125 µg/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/n-propyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Drug Design , Phenothiazines/pharmacology , Thiadiazoles/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Escherichia coli/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Mycobacterium tuberculosis/drug effects , Phenothiazines/chemistry , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Thiadiazoles/chemistry , Vero Cells
7.
Bioorg Med Chem Lett ; 25(19): 4169-73, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26298500

ABSTRACT

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 H37Rv 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.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Click Chemistry , Imidazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Thiadiazoles/pharmacology , Triazoles/pharmacology , Antitubercular Agents/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Imidazoles/chemistry , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemistry , Triazoles/chemistry
8.
Bioorg Med Chem Lett ; 25(14): 2768-72, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-26025875

ABSTRACT

A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 µM, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme.


Subject(s)
Histone Deacetylase Inhibitors/chemical synthesis , Indoles/chemistry , Isoxazoles/chemistry , Sirtuin 1/antagonists & inhibitors , Binding Sites , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , HEK293 Cells , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Protein Binding , Sirtuin 1/metabolism , Structure-Activity Relationship
9.
Eur J Med Chem ; 95: 49-63, 2015 May 05.
Article in English | MEDLINE | ID: mdl-25794789

ABSTRACT

In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by (1)H NMR, (13)C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 µg/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line.


Subject(s)
Antifungal Agents/pharmacology , Antioxidants/pharmacology , Antitubercular Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Thiadiazoles/chemistry , Tuberculosis/drug therapy , Animals , Antifungal Agents/chemical synthesis , Antioxidants/chemical synthesis , Antitubercular Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Cell Survival , Chlorocebus aethiops , Microbial Sensitivity Tests , Mycobacterium tuberculosis/growth & development , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Tuberculosis/microbiology , Vero Cells
10.
Eur J Med Chem ; 69: 125-38, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24013412

ABSTRACT

In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia.


Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Hyperplasia/drug therapy , Indoles/pharmacology , Sirtuin 1/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HEK293 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Hyperplasia/chemically induced , Indoles/chemical synthesis , Indoles/chemistry , K562 Cells , Male , Models, Molecular , Molecular Structure , Rats , Rats, Wistar , Sirtuin 1/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Testosterone
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