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The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

November 22, 2017 9:58 am / Leave a comment

CAS 74102-02-6

Molecular Formula:	C₁₅H₁₇NO₃
Molecular Weight:	259.305 g/mol

2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39): White solid; m.p. 249 o C; TLC Rf value, 0.48 (in EtOAc:Hexane,60:40);

IR (neat) 2980, 2950, 1678, 1040 cm-1;

1 H NMR (400 MHz, CD3OD) δ 9.86 (1H, bs), 8.66 (1H, d, J = 16.0 Hz), 7.46- 7.34 (1H, m), 7.07-6.84 (3H, m), 2.46 (2H, s), 2.41 (2H, s), 1.10 (3H, s), 1.09 (3H, s);

13C NMR (101 MHz, CDCl3) δ 199.8, 197.2, 149.6, 149.3, 147.8, 127.2, 126.6, 120.6, 120.3, 108.

The synthesis, biological evaluation and structure–activity relationship of 2-phenylaminomethylene-cyclohexane-1,3-diones as specific anti-tuberculosis agents

Muzafar Ahmad Rather,^a^b Ali Mohd Lone,^c Bisma Teli,^c^d Zubair Shanib Bhat,^a^d Paramjeet Singh,^e Mubashir Maqbool,^a Bashir Ahmad Shairgojray,^c Mohd Jamal Dar,^d^e Shajrul Amin,^b Syed Khalid Yousuf,*^c^d Bilal A. Bhat*^c^d and Zahoor Ahmad*^a^d

Author affiliations

*Corresponding authors

^aClinical Microbiology and PK/PD Division, Clinical Microbiology PK/PD/Laboratory, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, India-190005
E-mail: zahoorap@iiim.ac.in
Fax: +91 1942441331
Tel: +91 194 2431253/55

^bDepartment of Biochemistry, University of Kashmir, Hazratbal Srinagar, India-190006

^cMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, India-190005
E-mail: khalidiiim@gmail.com, bilal@iiim.ac.in
Fax: +91 194244133
Tel: +91 1942431253/55

^dAcademy of Scientific & Innovative Research (AcSIR), India

^eCancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, India-180001

Abstract

The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against Mycobacterium tuberculosis H37Rv (M. tuberculosis) and identified the cyclohexane-1,3-dione-based structures 5 and 6 as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against M. tuberculosis lead to the identification of three lead antituberculosis agents (37, 39 and 41). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (39) showed an MIC of 2.5 μg mL⁻¹, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria and even against M. smegmatis; thereby reflecting its highly specific antituberculosis activity.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/MD/C7MD00350A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

Muzafar Ahmad Rather

Ph.D Research Scholar

CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Srinagar

Clinical Microbiology and PK/PD Division, Clinical Microbiology PK/PD/Laboratory, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar, India-190005

Image result for Zahoor Ahmad CSIR

CSIR-Indian Institute of Integrative Medicine

(Council of Scientific & Industrial Research)

Dr. Zahoor Ahmad Parry

Clinical Microbiology Division
CSIR – Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: zahoorap@iiim.ac.in

Positions Held

Position Held	Date	Organization
Sr. Scientist	2010 – Present	CSIR-IIIM

Dr. Bilal Ahmad Bhat

Medicinal Chemistry Division
CSIR – Indian Institute of Integrative Medicine,Canal Road, Jammu – 180001
Email: bilal@iiim.ac.in

Positions Held

Position Held	Date	Organization
Scientist	2010 – Present	CSIR-IIIM

Image result for Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar,

Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Sanatnagar, Srinagar,

A small Drug Research Laboratory working under the Government of Jammu & Kashmir was taken over by CSIR in 1957 and named as Regional Research Laboratory, Jammu. Col. Sir Ram Nath Chopra, who is acclaimed the father of modern Pharmacology in India, was the Director of Drug Research Laboratory, continued as the first Director of Regional Research Laboratory. Having significant expertise in the area of medicinal & aromatic plants, Col. Chopra started its related R&D activities such as collection of plants from north & north-west and study the chemistry & pharmacology of the plant extracts and the new molecules isolated from these plants. Thus the initial mandate of this laboratory was mainly focused on screening the flora of north India for new molecules and to study the biological activity of these molecules. Gradually the activities of the institute increased, many more disciplines were introduced, that were important for the exploitation of regional resources such as mineral technology division, paper & pulp, fur technology division, sericulture, food technology division and mycology division. The main stream department such as chemistry, botany and pharmacology were strengthened by the introduction of a small animal house, instrumentation and chemical engineering & design division. The activity of the institute gradually increased which showed up in its publications and technology developments.

With the progress of time, the institute developed high quality expertise and infrastructure for working in the area of plant based products & drugs to explore new botanicals for new molecules and new activity. The institute specialized for working in the area of chemistry of natural products, synthesis of new & nature like molecules. These were studied for their use on various indication such as Oncology, hepatoprotection, anti-bacterial, bio-enhancers, anti-diabetes, anti-inflammation, aphrodisiac, hypertension, immunomodulation, anti-oxidants, oral care and beauty care. Some of the areas which did not progress to the satisfaction level gradually became redundant and were dropped.

Keeping in view the expertise developed in the area of natural products and revised mandate of the institute to explore and exploit natural, nature like and synthetic products with modern scientific tools to reduce the burden of disease, the institute became more focused towards integrative medicine hence was renamed as Indian Institute of Integrative Medicine in 2007 by the governing body of CSIR

////////////////// synthesis, biological evaluation, structure–activity relationship, 2-phenylaminomethylene-cyclohexane-1,3-diones, anti-tuberculosis agents

O=C2CC(C)(C)CC(=O)/C2=C\Nc1ccccc1O

DISCLAIMER

“NEW DRUG APPROVALS ” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

The greening of peptide synthesis

April 4, 2017 10:19 am / Leave a comment

The greening of peptide synthesis

Stefan B. Lawrenson,^a Roy Arav^a and Michael North*^a

*Corresponding authors

^aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York, York, UK
E-mail: Michael.north@york.ac.uk

Abstract

The synthesis of peptides by amide bond formation between suitably protected amino acids is a fundamental part of the drug discovery process. However, the required coupling and deprotection reactions are routinely carried out in dichloromethane and DMF, both of which have serious toxicity concerns and generate waste solvent which constitutes the vast majority of the waste generated during peptide synthesis. In this work, propylene carbonate has been shown to be a green polar aprotic solvent which can be used to replace dichloromethane and DMF in both solution- and solid-phase peptide synthesis. Solution-phase chemistry was carried out with Boc/benzyl protecting groups to the tetrapeptide stage, no epimerisation occurred during these syntheses and chemical yields for both coupling and deprotection reactions in propylene carbonate were at least comparable to those obtained in conventional solvents. Solid-phase peptide synthesis was carried out using Fmoc protected amino acids on a ChemMatrix resin and was used to prepare the biologically relevant nonapeptide bradykinin with comparable purity to a sample prepared in DMF.

Boc-Ala-Phe-OBn 5a ref S1

Boc-Ala-OH (324 mg, 1.71 mmol) and HCl.H-Phe-OBn (500 mg, 1.71 mmol) were coupled according to the general coupling procedure. The residue was purified using flash column chromatography (35:65, EtOAc:PE) to give Boc-Ala-Phe-OBn 5a as a white crystalline solid (682 mg, 93%). RF = 0.34 (40:60, EtOAc:PE);

mp 95.6-96.3 °C;

[α]D 23 -27.7 (c 1.0 in MeOH);

IR (Neat) νmax 3347 (m), 3063 (w), 3029 (w), 2928 (m), 2852 (w), 1735 (w), 1684

1666

and 1521 (s) cm-1;

1H NMR (400 MHz, CDCl3): δ = 7.36-7.31 (m, 3H, ArH), 7.29-7.24 (m, 2H, ArH), 7.26-7.21 (m, 3H, ArH), 7.04-6.97 (m, 2H, ArH), 6.72 (d J 7.7 Hz, 1H, Phe-NH), 5.16-5.10 (m, 1H, Ala-NH), 5.13 (d J 12.1 Hz, 1H, OCH2Ph), 5.07 (d J 12.1 Hz, 1H, OCH2Ph), 4.88 (dt, J 7.7, 5.9 1H, PheNCH), 4.11 (br, 1H, Ala-NCH), 3.13 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 3.08 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 1.41 (s, 9H, C(CH3)3), 1.29 (d J 6.6 Hz, 3H, CH3);

13C NMR (100 MHz, CDCl3): δ = 172.3 (C=O), 171.2 (C=O), 155.6 (NC=O), 135.7 (ArC), 135.1 (ArC), 129.5 (ArCH), 128.7 (ArCH), 128.6 (ArCH), 127.2 (ArCH), 80.2 (CMe3), 67.4 (OCH2Ph), 53.3 (Phe-NCH), 50.3 (Ala-NCH), 38.0 (CH2Ph), 28.4 (C(CH3)3), 18.5 (CH3);

MS (ESI) m/z 449 [(M+Na)+ , 100]; HRMS (ESI) m/z calculated for C24H30N2O5Na 449.2048 (M+Na)+ , found 449.2047 (0.6 ppm error).

S1 J. Nam, D. Shin, Y. Rew and D. L. Boger, J. Am. Chem. Soc., 2007, 129, 8747–8755; Q. Wang, Y. Wang and M. Kurosu, Org. Lett., 2012, 14, 3372–3375.

General procedure for peptide coupling reactions in PC To a suspension of an N-Boc-amino acid (1.0 eq.) and an amino acid or peptide benzyl ester (1.0 eq.) in PC (5 mL mmol-1), at 0 °C, was added a solution of HOBt (1.1 eq.) and i Pr2EtN (3.0 eq.) in a minimal quantity of PC. EDC (1.1 eq.) was added dropwise and the reaction mixture was allowed to stir at room temperature for 16h. The reaction mixture was then diluted using EtOAc (50 mL) and washed with 1M HClaq (3 × 25 mL), saturated Na2CO3 (3 × 25 mL) and H2O (3 × 25 mL). The organic layer was dried (MgSO4 ), filtered and concentrated in vacuo. Any residual PC was removed via short path distillation. Purification details for each peptide and characterising data are given in the supplementary information. General procedure for Boc deprotections in PC An N-Boc-peptide benzyl ester (1.0 eq.) was dissolved in a minimum amount of PC and trifluoroacetic acid (60 eq.) was added. The reaction mixture was allowed to stir for 3h. at room temperature before being concentrated in vacuo. Any residual PC was removed via short path distillation. Characterising data for each deprotected peptide are given in the supplementary information.

Procedure for Boc deprotection of dipeptide 5a using HCl in PC Boc-Ala-Phe-OBn 5a (50 mg, 0.117 mmol) was dissolved in PC (2.34 mL). MeOH (0.40 mL, 9.8 mmol) was added and the solution cooled to 0 o C. Acetyl chloride (0.67 mL, 9.36 mmol) was added dropwise and the solution allowed to stir at room temperature for 2h. Then, PC was removed by short path distillation. The residue was suspended in Et2O and stirred for 5 minutes before being filtered to give HCl.Ala-Ph-OBn as a white solid (32.4 mg, 76%).

Propylene carbonate 1 has been shown to be a green replacement for reprotoxic amide based solvents which are widely used in peptide synthesis. Both solution- and solidphase peptide synthesis can be carried out in propylene carbonate using acid and base labile amine protecting groups respectively. No significant racemisation of the activated amino acids occurs in propylene carbonate and the viability of solid-phase peptide synthesis in propylene carbonate was demonstrated by the synthesis of the nonapeptide bradykinin.

///////////

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

January 5, 2016 12:59 pm / Leave a comment

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

1 Diphenhydramine Hydrochloride

Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride

Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.

In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.

The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Scheme 2. Continuous Flow Synthesis of Olanzapine

Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.

In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd₂dba₃ as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H₂O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et₃SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.

The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)₄ as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Riccardo Porta, Maurizio Benaglia^*, and Alessandra Puglisi^*

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00325

Publication Date (Web): November 26, 2015

*E-mail: maurizio.benaglia@unimi.it., *E-mail: alessandra.puglisi@unimi.it.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00325

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

University of Milan

Department of Chemistry

Milano, Italy

Maurizio Benaglia

University of Milan, Milano · Department of Chemistry

Riccardo Porta

PhD Student

University of Milan, Milano · Department of Chemistry

Alessandra Puglisi

University of Milan, Milano · Department of Chemistry

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Map of milan italy

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New Route to Anticancer Agent Quinocarcin

May 24, 2013 3:47 am / 3 Comments on New Route to Anticancer Agent Quinocarcin

Compound Structure

Quinocarcin,

Antibiotic DC 52, DC 52, CHEBI:554143, CID158486, LS-80981, 3,6-Imino-1H-2-oxa-11c-azanaphth(1,2,3-cd)azulene-5-carboxylic acid, 2a,3,4,5,6,6a,7,11b-octahydro-11-methoxy-12-methyl-, (2a-alpha,3-alpha,5-alpha,6-alpha,6a-alpha,11b-alpha)-, (-)-, 84573-33-1

Synthesis of quinocarcin through a convergent strategy based on Sonogashira coupling and gold(I)-catalyzed hydroamination

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Abstract

Muzafar Ahmad Rather

CSIR-Indian Institute of Integrative Medicine (CSIR-IIIM), Srinagar

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Abstract

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Two examples out of several in the publication discussed below……………

1 Diphenhydramine Hydrochloride

2 Olanzapine

SEE MORE IN THE PUBLICATION…………..

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

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