MyMedR

Structural Modifications of Benzimidazoles via Multi-Step Synthesis and Their Impact on Sirtuin-Inhibitory Activity

Yoon YK, Choon TS

Arch Pharm (Weinheim), 2016 Jan;349(1):1-8.

PMID: 26616218 DOI: 10.1002/ardp.201500337

Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed.

Fulltext A Cell Internalizing Antibody Targeting Capsid Protein (p24) Inhibits the Replication of HIV-1 in T Cells Lines and PBMCs: A Proof of Concept Study

Ali SA, Teow SY, Omar TC, Khoo AS, Choon TS, Yusoff NM

PLoS One, 2016;11(1):e0145986.

PMID: 26741963 DOI: 10.1371/journal.pone.0145986

There remains a need for newer therapeutic approaches to combat HIV/AIDS. Viral capsid protein p24 plays important roles in HIV pathogenesis. Peptides and small molecule inhibitors targeting p24 have shown to inhibit virus replication in treated cell. High specificity and biological stability of monoclonal antibodies (mAbs) make them an attractive contender for in vivo treatments. However, mAbs do not enter into cells, thus are restricted to target surface molecules. This also makes targeting intracellular HIV-1 p24 a challenge. A mAb specific to p24 that can internalize into the HIV-infected cells is hypothesized to inhibit the virus replication. We selected a mAb that has previously shown to inhibit p24 polymerization in an in vitro assay and chemically conjugated it with cell penetrating peptides (CPP) to generate cell internalizing anti-p24 mAbs. Out of 8 CPPs tested, κFGF-MTS -conjugated mAbs internalized T cells most efficiently. At nontoxic concentration, the κFGF-MTS-anti-p24-mAbs reduced the HIV-1 replication up to 73 and 49% in T-lymphocyte and PBMCs respectively. Marked inhibition of HIV-1 replication in relevant cells by κFGF-MTS-anti-p24-mAbs represents a viable strategy to target HIV proteins present inside the cells.

Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties

Yoon YK, Ali MA, Wei AC, Shirazi AN, Parang K, Choon TS

Eur J Med Chem, 2014 Aug 18;83:448-54.

PMID: 24992072 DOI: 10.1016/j.ejmech.2014.06.060

Two series of novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. Among the newly synthesized compounds, compound 4j displayed the best inhibitory activity for SIRT1 (IC50 = 54.21 μM) as well as for SIRT2 (IC50 = 26.85 μM). Cell proliferation assay showed that compound 4j possessed good antitumor activity against three different types of cancer cells derived from colon (HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM) with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 μM. Docking analysis of representative compound 4j into SIRT2 indicated that the interaction with receptor was primarily due to hydrogen bonding and π-π stacking interactions.

Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters

Yoon YK, Ali MA, Wei AC, Choon TS, Ismail R

Eur J Med Chem, 2015 Mar 26;93:614-24.

PMID: 24996257 DOI: 10.1016/j.ejmech.2013.06.025

A total of 51 novel benzimidazoles were synthesized by a 4-step reaction starting from basic compound 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The structure of the novel benzimidazoles was confirmed by mass spectra as well as (1)H NMR spectroscopic data. Out of the 51 novel synthesized compounds, 42 of them were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain using BacTiter-Glo™ Microbial Cell Viability (BTG) method. Results of activity screened using Alamar Blue method was also provided for comparison purposes. Two of the novel benzimidazoles synthesized showed moderately good activity with IC50 of less than 15 μM. Compound 5g, ethyl 2-(4-(trifluoromethyl)phenyl)-1-(2-morpholinoethyl)-1H-benzo[d]imidazole-5-carboxylate, was found to be the most active with IC50 of 11.52 μM.

Sequential synthesis of amino-1,4-naphthoquinone-appended triazoles and triazole-chromene hybrids and their antimycobacterial evaluation

Devi Bala B, Muthusaravanan S, Choon TS, Ashraf Ali M, Perumal S

Eur J Med Chem, 2014 Oct 6;85:737-46.

PMID: 25129868 DOI: 10.1016/j.ejmech.2014.08.009

A general method for the synthesis of a library of hitherto unreported amino-1,4-naphthoquinone-appended triazoles was accomplished via a sequential three-component reaction of substituted N-propargylaminonaphthoquinones with variously substituted alkyl bromides/2-bromonaphthalene-1,4-dione and sodium azide in the presence of Et3N/CuI in water. Aminonaphthoquinone-appended iminochromene-triazole hybrid heterocycles were also synthesized from the amino-1,4-naphthoquinone-appended-1,2,3-triazolylacetonitriles. All the triazole hybrids were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among the triazoles, 2-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)(4-(trifluoromethyl)phenyl)amino)naphthalene-1,4-dione (7d) emerged as the most active one with IC50 = 1.87 μM, being more potent than the anti-TB drugs, cycloserine (6 times), pyrimethamine (20 times) and equipotent as the drug ethambutol (IC50

Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

Yoon YK, Ali MA, Wei AC, Choon TS, Osman H, Parang K, et al.

Bioorg Med Chem, 2014 Jan 15;22(2):703-10.

PMID: 24387981 DOI: 10.1016/j.bmc.2013.12.029

A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.

Fulltext Ethyl 2-[5-(4-fluoro-phen-yl)pyridin-3-yl]-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H-benzimidazole-5-carboxyl-ate

Yeong KY, Ali MA, Choon TS, Rosli MM, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2013;69(Pt 7):o1013-4.

PMID: 24046597 DOI: 10.1107/S1600536813014177

In the title compound, C28H27FN4O3·H2O, the benzimidazole ring system is essentially planar with a maximum deviation of 0.028 (1) Å. It makes dihedral angles of 47.59 (5) and 60.31 (5)°, respectively, with the pyridine and benzene rings, which make a dihedral angle of 22.58 (6)° with each other. The pyrrolidine ring shows an envelope conformation with one of the methyl-ene C atoms as the flap. In the crystal, the components are connected into a tape along the b-axis direction through O-H⋯O and O-H⋯N hydrogen bonds and a π-π inter-action between the pyridine and benzene rings [centroid-centroid distance of 3.685 (8) Å]. The tapes are further linked into layers parallel to the ab plane by C-H⋯O and C-H⋯F inter-actions.

Fulltext Ethyl 2-[4-(di-methyl-amino)-phen-yl]-1-phenyl-1H-benzimidazole-5-carboxyl-ate

Yeong KY, Ali MA, Choon TS, Rosli MM, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2013 Jun 1;69(Pt 6):o886.

PMID: 23795062 DOI: 10.1107/S1600536813012440

In the title compound, C24H23N3O2, the benzimidazole ring system makes dihedral angles of 7.28 (5) and 67.17 (5)°, respectively, with the planes of the benzene and phenyl rings, which in turn make a dihedral angle of 69.77 (6)°. In the crystal, mol-ecules are connected by C-H⋯N and C-H⋯O inter-actions, forming a layer parallel to the bc plane. A π-π inter-action, with a centroid-centroid distance of 3.656 (1) Å, is observed in the layer.

Fulltext 4'-(4-Fluoro-phen-yl)-1'-methyl-dispiro-[indane-2,2'-pyrrolidine-3',2''-indane]-1,3,1''-trione methanol hemisolvate

Ali MA, Manogaran E, Choon TS, Rosli MM, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2013 May 1;69(Pt 5):o746-7.

PMID: 23723896 DOI: 10.1107/S1600536813009987

The asymmetric unit of the title compound, C29H24FNO5·0.5CH3OH, contains two independent mol-ecules and a one methanol solvent mol-ecule. The methanol mol-ecule is O-H⋯O hydrogen bonded to one of the independent mol-ecules. The pyrrolidine rings in both mol-ecules adopt half-chair conformations, while the cyclo-pentane rings within the indane groups are in flattened envelope conformations, with the spiro C atoms forming the flaps. The benzene rings of the indane ring systems form a dihedral angle of 35.06 (7)° in one independent mol-ecule and 31.16 (8)° in the other. The fluoro-substituted benzene ring forms dihedral angles of 65.35 (6) and 85.87 (7)° with the indane group benzene rings in one mol-ecule, and 72.78 (8) and 77.27 (8)° in the other. In each mol-ecule, a weak intra-molecular C-H⋯O hydrogen bond forms an S(6) ring motif. In the crystal, weak C-H⋯O, C-H⋯N and C-H⋯F hydrogen bonds link the mol-ecules into a three-dimensional network.

Fulltext 4'-(3-Bromo-phen-yl)-1'-methyl-dispiro-[indan-2,2'-pyrrolidine-3',2''-indan]-1,3,1''-trione

Wei AC, Ali MA, Choon TS, Arshad S, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2012 Oct 1;68(Pt 10):o2907-8.

PMID: 23125700 DOI: 10.1107/S1600536812037993

In the title compound, C(27)H(20)BrNO(3), two intra-molecular C-H⋯O hydrogen bonds both form S(6) rings. The pyrrolidine ring adopts a twisted conformation about the C-C bond bearing the indane ring systems. The other two five-membered rings within the indane systems are in shallow envelope conformations, with the spiro C atoms as the flap atoms. The mean plane of the pyrrolidine ring [maximum deviation = 0.275 (1) Å] makes dihedral angles of 65.25 (7), 78.33 (6) and 75.25 (6)° with the bromo-substituted benzene ring and the mean planes of the mono- and dioxo-substituted indane rings, respectively. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯N hydrogen bonds into a three-dimensional network. In addition, C-H⋯π inter-actions are observed.

Fulltext Ethyl 2-[4-(morpholin-4-yl)phen-yl]-1-[3-(2-oxopyrrolidin-1-yl)prop-yl]-1H-1,3-benzimidazole-5-carboxyl-ate monohydrate

Yoon YK, Ali MA, Choon TS, Arshad S, Razak IA

Acta Crystallogr Sect E Struct Rep Online, 2012 Oct 1;68(Pt 10):o2967-8.

PMID: 23125749 DOI: 10.1107/S1600536812039268

The asymmetric unit of the title compound, C(27)H(32)N(4)O(4)·H(2)O, contains two independent benzimidazole-5-carboxyl-ate mol-ecules and two water mol-ecules. In both main mol-ecules, the pyrrolidine rings are in an envelope conformation with a methyl-ene C atom as the flap. The morpholine rings adopt chair conformations. Both benzimidazole rings are essentially planar, with maximum deviations of 0.008 (1) Å, and form dihedral angles of 37.65 (6) and 45.44 (6)° with the benzene rings. In one mol-ecule, an intra-molecular C-H⋯O hydrogen bond forms an S(7) ring motif. In the crystal, O-H⋯O and O-H⋯N hydrogen bonds connect pairs of main mol-ecules and pairs of water mol-ecules into two independent centrosymmetric four-compoment aggregates. These aggregates are connect by C-H⋯O hydrogen bonds leading to the formation of a three-dimensional network, which is stabilized by C-H⋯π interactions.

Antimycobacterial activity: synthesis of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues

Ali MA, Ismail R, Choon TS, Pandian S, Hassan Ansari MZ

J Enzyme Inhib Med Chem, 2011 Aug;26(4):598-602.

PMID: 21714764 DOI: 10.3109/14756366.2010.529805

In this study, a series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized and evaluated for antimycobacterial activity against Mycobacterium tuberculosis (MTB) H(37)Rv and isoniazid resistant M. tuberculosis (INHR-MTB). All the newly synthesized compounds were showing moderate to high inhibitory activities. The compound 6,7-dimethoxy-3-(4-chloro phenyl)-4H-indeno[1,2-c]isoxazole (4b) was found to be the most promising compound, active against MTB H(37)Rv and INHR-MTB with minimum inhibitory concentrations of 0.22 and 0.34 μM.

Report: Demographic profiles and sleep quality among patients on methadone maintenance therapy (MMT) in Malaysia

Zahari Z, Siong LC, Musa N, Mohd Yasin MA, Choon TS, Mohamad N, et al.

Pak J Pharm Sci, 2016 Jan;29(1):239-46.

PMID: 26826835

Poor sleep quality was frequently reported by opioid dependence patients during methadone maintenance therapy (MMT). The study investigated a sample of patients on MMT to investigate the severity and prevalence of sleep problems in MMT patients. We evaluated sleep quality and disturbances of 119 Malay male patients from MMT clinics in Kelantan, Malaysia between March and July 2013 using the Pittsburgh Sleep Quality Index (PSQI)-Malay version. Patients' demographic, clinical data, past drug history and methadone treatment variables were recorded. Patients averaged 37.5 years of age (SD 6.79) and their mean age of first time illicit drug use was 19.3 years (SD 4.48). Their mean age of entering MMT was 34.7 years (SD 6.92) and the mean duration in MMT was 2.8 years (SD 2.13). The mean current daily dosage of methadone was 77.8 mg (SD 39.47) and ranged from 20 to 360 mg. The mean global PSQI score was 5.6 (SD 2.79) and 43.7% patients were identified as 'poor sleepers' (global PSQI scores >5). This study confirms the poor overall sleep quality among patients on MMT. The prevalence and severity of sleep problems in MMT patients should not be underestimated.

A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents

Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS

Bioorg Med Chem Lett, 2013 Mar 1;23(5):1383-6.

PMID: 23352268 DOI: 10.1016/j.bmcl.2012.12.069

A series of fourteen dispiropyrrolidines were synthesized using [3+2]-cycloaddition reactions and were screened for their antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv in HTS (High Throughput Screen). Most of the compounds showed moderate to good activity with MIC of less than 20 μM. Compound 4'-(4-bromophenyl)-1'-methyldispiro[acenaphthylene-1,2'-pyrrolidine-3',2″-indane]-2,1″(1H)-dione (4c) was found to be the most active with MIC of 12.50 μM.

Antimycobacterial evaluation of novel hybrid arylidene thiazolidine-2,4-diones

Ponnuchamy S, Kanchithalaivan S, Ranjith Kumar R, Ali MA, Choon TS

Bioorg Med Chem Lett, 2014 Feb 15;24(4):1089-93.

PMID: 24472146 DOI: 10.1016/j.bmcl.2014.01.007

A series of novel hybrid heterocycles comprising arylidene thiazolidine-2,4-dione and 1-cyclopropyl-2-(2-fluorophenyl)ethanone were synthesized. These compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv in High Throughput Screen. Most of the hybrid arylidene thiazolidine-2,4-diones displayed moderate to good activity with MIC of less than 50 μM. Compound 1m exhibited maximum potency being 5.87 fold more active at EC50 and 6.26 fold more active at EC90 than the standard drug pyrimethamine.

Population pharmacokinetics of nevirapine in Malaysian HIV patients: a non-parametric approach

Mustafa S, Yusuf WN, Woillard JB, Choon TS, Hassan NB

Eur J Clin Pharmacol, 2016 Jul;72(7):831-8.

PMID: 27025609 DOI: 10.1007/s00228-016-2049-6

AIMS: Nevirapine is the first non-nucleoside reverse-transcriptase inhibitor approved and is widely used in combination therapy to treat HIV-1 infection. The pharmacokinetics of nevirapine was extensively studied in various populations with a parametric approach. Hence, this study was aimed to determine population pharmacokinetic parameters in Malaysian HIV-infected patients with a non-parametric approach which allows detection of outliers or non-normal distribution contrary to the parametric approach.

METHODS: Nevirapine population pharmacokinetics was modelled with Pmetrics. A total of 708 observations from 112 patients were included in the model building and validation analysis. Evaluation of the model was based on a visual inspection of observed versus predicted (population and individual) concentrations and plots weighted residual error versus concentrations. Accuracy and robustness of the model were evaluated by visual predictive check (VPC). The median parameters' estimates obtained from the final model were used to predict individual nevirapine plasma area-under-curve (AUC) in the validation dataset. The Bland-Altman plot was used to compare the AUC predicted with trapezoidal AUC.

RESULTS: The median nevirapine clearance was of 2.92 L/h, the median rate of absorption was 2.55/h and the volume of distribution was 78.23 L. Nevirapine pharmacokinetics were best described by one-compartmental with first-order absorption model and a lag-time. Weighted residuals for the model selected were homogenously distributed over the concentration and time range. The developed model adequately estimated AUC.

CONCLUSIONS: In conclusion, a model to describe the pharmacokinetics of nevirapine was developed. The developed model adequately describes nevirapine population pharmacokinetics in HIV-infected patients in Malaysia.

Fulltext Antituberculosis: synthesis and antimycobacterial activity of novel benzimidazole derivatives

Keng Yoon Y, Ashraf Ali M, Choon TS, Ismail R, Chee Wei A, Suresh Kumar R, et al.

Biomed Res Int, 2013;2013:926309.

PMID: 24381946 DOI: 10.1155/2013/926309

A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H₃₇Rv (MTB-H₃₇Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5 g) was found to be the most active with MIC of 0.112 μM against MTB-H₃₇Rv and 6.12 μM against INHR-MTB, respectively.

Synthesis, characterization, and molecular docking analysis of novel benzimidazole derivatives as cholinesterase inhibitors

Yoon YK, Ali MA, Wei AC, Choon TS, Khaw KY, Murugaiyah V, et al.

Bioorg Chem, 2013 Aug;49:33-9.

PMID: 23886696 DOI: 10.1016/j.bioorg.2013.06.008

Two series of novel acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors containing benzimidazole core structure were synthesized by a four-step reaction pathway starting from 4-fluoro-3-nitrobenzoic acid as the basic compound. The structure of the novel benzimidazoles was characterized and confirmed by the elemental and mass spectral analyses as well as (1)H NMR spectroscopic data. Of the 34 novel synthesized compounds, three benzimidazoles revealed AChE inhibition with IC50<10 μM. The highest inhibitory activity (IC50=5.12 μM for AChE and IC50=8.63 μM for BChE) corresponds to the compound 5IIc (ethyl 1-(3-(1H-imidazol-1-yl)propyl)-2-(4-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate). The relationship between lipophilicity and the chemical structures as well as their limited structure-activity relationship was discussed.

Fulltext Synthesis and anti-HIV activity of novel 3-substituted phenyl-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues

Ali MA, Ismail R, Choon TS, Yoon YK, Wei AC, Pandian S, et al.

Acta Pol Pharm, 2011 May-Jun;68(3):343-8.

PMID: 21648188

A series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized by the reaction of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-indanone with hydroxylamine hydrochloride. The title compounds were tested for their in vitro anti-HIV activity. Among the compounds, (4g) showed a promising anti-HIV activity in the in vitro testing against IIIB and ROD strains. The IC50 of both IIIB and ROD were found to be 9.05 microM and > 125 microM, respectively.

Discovery of novel methanone derivatives acting as antimycobacterial agents

Ali MA, Bastian S, Ismail R, Choon TS, Ali S, Aubry A, et al.

J Enzyme Inhib Med Chem, 2011 Dec;26(6):890-4.

PMID: 21395486 DOI: 10.3109/14756366.2011.559945

A series of pyrazoline derivatives were synthesized and in vitro activity against Mycobacterium tuberculosis H37Rv was carried out. Among the synthesized compounds, compounds (4d) and (4f) 4-aminophenyl-3-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone and 4-aminophenyl-6,7-dimethoxy-3-phenyl-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone were found to be the most active agent against M. tuberculosis H37Rv with a minimum inhibitory concentration of 10 μg/mL.

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