DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463,

Sep 202017


Catalyst-free multi-component cascade C-H-functionalization in water using molecular oxygen: an approach to 1,3-oxazines

Green Chem., 2017, 19,4036-4042
DOI: 10.1039/C7GC01494E, Communication
Mohit L. Deb, Choitanya D. Pegu, Paran J. Borpatra, Prakash J. Saikia, Pranjal K. Baruah
Synthesis of 1,3-oxazines via catalyst free C-H functionalization using molecular oxygen in water.

Catalyst-free multi-component cascade C–H-functionalization in water using molecular oxygen: an approach to 1,3-oxazines

 Author affiliations


Herein, catalyst-free 3-component reactions of naphthols, aldehydes, and tetrahydroisoquinolines to synthesize 1,3-oxazines is reported. The reaction is performed in H2O in the presence of O2 as the sole oxidant at 100 °C, which proceeds through the formation of 1-aminoalkyl-2-naphthols followed by selective α-C–H functionalization of tert-amine.

15-phenyl-7a,12,13,15-tetrahydronaphtho[1′,2′:5,6][1,3]oxazino[2,3- a]isoquinoline (4a):1

White solid; Yield 61 %, 221 mg;

1H NMR (500 MHz, CDCl3): δ 7.79-7.77 (m, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.43-7.41 (m, 1H), 7.33-7.28 (m, 8H), 7.24-7.19 (m, 3H), 7.11 (d, J = 8.9 Hz, 1H), 5.65 (s, 1H), 5.44 (s, 1H), 3.40-3.26 (m, 2H), 3.12-3.09 (m, 1H), 2.90- 2.86 (m, 1H);

13C NMR (125 MHz, CDCl3): δ 151.9, 142.3, 135.0, 133.0, 132.4, 129.3, 129.1, 128.9, 128.8 (2C), 128.7, 128.6, 128.2, 127.4, 126.5, 126.2, 123.1, 122.7, 118.9, 110.9, 82.2, 62.6, 45.4, 29.4;

HRMS (ESI) exact mass calculated for C26H21NO [M+H]+ : 364.1701; found: 364.1705.

The representative procedure for the synthesis of 4a is as follows: 2-naphthol (1a, 144 mg, 1 mmol), benzaldehyde (2a, 106 mg, 1 mmol), tetrahydroisoquinoline (3, 133 mg, 1 mmol) and water (1.5 mL) were added in a round-bottom flask equipped with a magnetic stirring bar and a reflux condenser. The whole apparatus was efficiently flushed with oxygen gas and then connected to a balloon filled with oxygen. After vigorous stirring at 100 oC for 12 h, water was removed under vacuum and purified the reaction mixture by column chromatography (100-200 mesh silica gel, hexane-ethyl acetate) to obtain the product 4a as white solid. The other 1,3-oxazines were synthesized and purified by following the procedure described above




Sep 162017


Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02211E, Paper
F. A. Kucherov, K. I. Galkin, E. G. Gordeev, V. P. Ananikov
Efficient one-pot synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described using a [4 + 2] cycloaddition reaction.

Efficient route for the construction of polycyclic systems from bioderived HMF

 Author affiliations


The first synthesis of tricyclic compounds from biobased 5-hydroxymethylfurfural (HMF) is described. The Diels–Alder reaction was used to implement the transition from HMF to a non-planar framework, which possessed structural cores of naturally occurring biologically active compounds and building blocks of advanced materials. A one-pot, three-step sustainable synthesis in water was developed starting directly from HMF. The reduction of HMF led to 2,5-bis(hydroxymethyl)furan (BHMF), which could be readily involved in the Diels–Alder cycloaddition reaction with HMF-derived maleimide, followed by hydrogenation of the double bond. The described transformation was diastereoselective and proceeded with a good overall yield. The applicability of the chosen approach for the synthesis of analogous structures containing amine functionality on the side chain was demonstrated. To produce the target compounds, only platform chemicals were used with carbohydrate biomass as the single carbon source.

Endo-4,7-bis(hydroxymethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (endo-4,7-bis(hydroxymethyl)norcantharimid-5-ene), 3

1H NMR (DMSO-d6) = 10.82 (s, 1H), 6.37 (s, 2H), 5.11 (t, 2H, J = 5.7 Hz), 3.97 (dd, 2H, J = 5.7 Hz, 12.8 Hz), 3.84 (dd, 2H, J = 5.7 Hz, 12.8 Hz), 3.44 (s, 2H);

13C NMR (DMSO-d6) = 176.9, 136.0, 92.1, 59.8, 48.8 ppm.

m/z HRMS (ESI) Calcd. for C10H11NO5 [M+Na]: 248.0529. Found 248.0536.


str4 str6




str4 str6



str4 str6



Sep 072017

Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02014G, Communication
Yanjun Xie, Xiangui Chen, Zhen Wang, Huawen Huang, Bing Yi, Guo-Jun Deng
Aerobic cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen under metal-free conditions.

Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen!divAbstract


Metal-free oxidative cyclization for the one-pot synthesis of benzo[d]imidazo[2,1-b]thiazoles from 2-aminobenzothiazoles and cyclic ketones is described. Elemental sulfur combined with molecular oxygen as the benign co-oxidant was found to be unique and highly effective to promote this transformation without the aid of any metal salts. Various cyclic ketones smoothly reacted with 2-aminobenzothiazoles to give functional benzo[d]imidazo[2,1-b]thiazoles in good to very high yields, which thereby demonstrated the synthetic convergence of this methodology.

Graphical abstract: Metal-free oxidative cyclization of 2-aminobenzothiazoles and cyclic ketones enabled by the combination of elemental sulfur and oxygen
7,8,9,10-Tetrahydrobenzo[d]benzo[4,5]imidazo[2,1-b]thiazole (3a)
White solid; yield: 39.2 mg (86%), mp 140-142 °C.
1H NMR (400 MHz, CDCl3, ppm) δ 7.67-7.62 (m, 2H), 7.38 (t, J = 7.76 Hz, 1H), 7.27 (t, J = 7.68 Hz, 1H), 3.07-3.04 (m, 2H), 2.77-2.74 (m, 2H), 2.00-1.95 (m, 2H), 1.92-1.86 (m, 2H);
13C NMR (100 MHz, CDCl3, ppm) δ 145.1, 142.4, 132.9, 129.7, 125.5, 123.9, 123.5, 121.8, 111.9, 24.8, 22.8, 22.7, 21.8;
MS (EI) m/z (%) 228, 200 (100), 160, 108, 51;
HRMS calcd. for: C13H13N2S + (M+H)+ 229.07940, found 229.07941.
cas 325766-28-7
C13 H12 N2 S, 228.31,  Benzimidazo[2,​1-​b]​benzothiazole, 7,​8,​9,​10-​tetrahydro-



Sep 012017


Image result for ncl pune


Route to Benzimidazol-2-ones via Decarbonylative Ring Contraction of Quinoxalinediones: Application to the Synthesis of Flibanserin, A Drug for Treating Hypoactive Sexual Desire Disorder in Women and Marine Natural Product Hunanamycin Analogue

 Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
 Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 025, India
ACS Omega, 2017, 2 (8), pp 5137–5141
DOI: 10.1021/acsomega.7b00819
*E-mail: Phone: +91-20-2590 2445 (D.S.R.).

ACS AuthorChoice – 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.


Benzimidazol-2-ones 1 are an important class of heterocycles and a privileged scaffold in medicinal chemistry. They consist of cyclic urea fused with the aromatic backbone, which can potentially interact in a biological system by various noncovalent interactions such as hydrogen bonding and π stacking. Benzimidazolone derivatives exhibit a wide range of biological activities, and they are useful in treating various diseases including cancer, type II diabetes, central nervous system disorders, pain management, and infectious disease.1 Selected compounds embedded with a benzimidazol-2-one moiety along with their use are captured in Figure 1. It is worth mentioning that oxatomide drug with a benzimidazol-2-one core was approved for marketing a few years ago.2a Very recently, US Food and Drug Administration approved a new drug called flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in females, which contains benzimidazol-2- one motif.2b


We have developed a mild and new protocol for the synthesis of benzimidazol-2-ones from quinoxalinediones through decarbonylation. The present methodology can be an addition to the toolbox to prepare benzimidazolones, and it will be useful in medicinal chemistry, particularly, late-stage functionalization of natural products, drug scaffolds, or an intermediate containing quinoxaline-2,3-diones. As direct application of this method, we have successfully developed a new route for the synthesis of recently approved drug flibanserin and a urea analogue of antibiotic natural product hunanamycin A. Later application demonstrates the utility of the present method in late-stage functionalization


Synthesis of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1,3-dihydro-2Hbenzo[d]imidazol-2-one (Flibanserin)

Flibanserin hydrochloride as white solid.

1H NMR (400MHz ,DMSO-d6)  11.06 (s, 1 H), 10.93 (br. s., 1 H), 7.54 – 7.41 (t, J = 7.9 Hz, 1 H), 7.36 – 7.22 (m, 3 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.09 – 7.01 (m, 3 H), 4.30 (t, J = 6.7 Hz, 2 H), 4.01 (d, J = 11.6 Hz, 2 H), 3.75 (d, J = 10.4 Hz, 2 H), 3.54 – 3.43 (d, J = 4.2 Hz 2 H), 3.31 – 3.10 (m, 4 H);

HRMS (ESI): m/z calculated for C20H22ON4F3[M+H]+ 391.1740 found 391.1743;



Scheme 4. Synthesis of Flibanserin through Ring Contraction

The same methodology was applied for the synthesis of flibanserin, also known as “female viagra”, which is the first approved medication for treating HSDD in women and is classified as a multifunctional serotonin agonist antagonist.(14, 15) Our synthesis of flibanserin commenced with 1-benzyl-1,4-dihydroquinoxaline-2,3-dione 36,(16) which was reacted with known chloride 37(17) under the basic condition in DMF to give the desired product 38 in good yield. Compound 38 was subjected for the decarbonylative cyclization under the optimized condition to afford the product 39 in 59% yield. Finally, the benzyl group was deprotected using trifluoromethanesulfonic acid in toluene under microwave irradiation,(8b, 18) which gave flibanserin in excellent yield (Scheme 4). The final product was isolated as HCl salt, and all of the spectral data are in agreement with the published data.(15c)

Image result for Rahul D. Shingare

Rahul D. Shingare completed his M.Sc  (Chemistry) from Fergusson College,  Pune  in 2008. He worked as a research associate in Ranbaxy and Lupin New drug discovery center, Gurgaon and Pune respectively until 2012 and currently pursuing his doctoral research in NCL – Pune from 2012.

Current Research Interests: Antibacterial Natural Product Hunanamycin A: Total Synthesis, SAR and Related Chemistry.









Akshay Kulkarni completed his M.Sc. from Ferguson College, Pune University in the year 2015 and joined our group as a Project Assistant in the month of October, 2015.

Current research interest: Synthesis of silicon incorporated biologically active antimalerial compounds.

e-mail :

Image result for Rahul D. Shingare


Dr.D. Srinivasa Reddy
Organic Chemistry Division
CSIR-National Chemical Laboratory

  1. 14.

    StahlS. M. Mechanism of action of Flibanserin, A multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder CNS Spectrums 2015201 DOI: 10.1017/s1092852914000832

  2. 15.

    See, previous synthesis of Flibanserin:

    (a) BiettiG.BorsiniF.TurconiM.GiraldoE.BignottiM. For treatment of central nervous system disorders. U.S. Patent 5,576,318, 1996.

    (b) MohanR. D.ReddyP. K.;ReddyB. V. Process for the preparation of Flibanserin involving novel intermediates. WO2010128516 A2,2010.

    (c) YangF.WuC.LiZ.TianG.WuJ.ZhuF.ZhangJ.HeY.ShenJ. A Facile route of synthesis for making Flibanserin Org. Process Res. Dev. 2016201576 DOI: 10.1021/acs.oprd.6b00108

  3. 16.

    JarrarA. A.FataftahZ. A. Photolysis of some quinoxaline-1,4-dioxides Tetrahedron 1977332127 DOI: 10.1016/0040-4020(77)80326-8

  4. 17.

    XueongX. Preparation method of Flibanserin. CN104926734 A, 2015.

  5. 18.

    RomboutsF.FrankenD.Martínez-LamencaC.BraekenM.ZavattaroC.ChenJ.TrabancoA. A.Microwave-assisted N-debenzylation of amides with triflic acid Tetrahedron Lett. 2010514815 DOI: 10.1016/j.tetlet.2010.07.022





Aug 252017




Dr. M. Sunitha Reddy*, CH.Soujanya, MD. Fazal ul Haq


ABSTRACT In the present study an attempt was made to increase the therapeutic effectiveness of losartan potassium,by increasing the solubility and dissolution rate via solid dispersion using β-cyclodextrin as carrier. Losartan potassium is an Antihypertensive agent but failed to show good therapeutic effect. Eight solid dispersion formulations of losartan potassium were prepared by using different drug:polymer ratios viz.1:2,1:2,1:3,1:4 by novel methods like Hot melt extrusion,Lyophilization.prepared solid dispersions were evaluated. The blend of all the formulations showed good flow properties such as angle of repose, bulk density, tapped density. All the solid dispersion formulations were compressed into orodispersible tablets with weight equivalent to losartan potassium of 25mg by direct compression method using 6mm punch on 8 station rotary tablet punching machine. The prepared tablets were evaluated for its hardness, disintegration, weight variation, friability and invitro dissolution studies.The Infra Red spectra revealed that there is no incompatability between the drug and excipients. The prepared tablets were shown good post compression parameters and they passed all the quality control evaluation parameters as per I.P limits. Among all the formulations F4 and F8 formulations showed maximum % drug release i.e.93.83%(Lyophilization), 97.10%(Hot melt extrusion method) within 45min.these are compared with pure drug which shows %drug release58.67%. The optimized formulations were subjected to different kinetic models.the formulations were found to follow zero order release. optimized formulations Were subjected to Accelerated stability study for 3 months according to ICH guidelines.The results found to satisfactory.
Considering all evaluation parameters and % drug release F8 formulation shown better % drug release compared with F4 formulation. hence F8 formulation considered as optimised formulation.
KEYWORDS: Losartan potassium, β-cyclodextrin, solid dispersion, Lyophilization, Hot melt extrusion. FTIR.
CONCLUSION Losartan potassium is belongs to class II drugs, that is, characterized by low solubility and low permeability therefore, the enhancement of its solubility and dissolution profile is  expected to significantly improve its bioavailability and reduce its side effects. The precompression blends of Losartan were characterized with respect to angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. The precompression blend of all the batches indicates well to fair flowability and compressibility. Among all the formulations F8 formulation, showed good result that is 97.10 % in 45 minutes. As the concentration of polymer increases the drug release was decreased.
Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India
Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India

Lifetime achievement award, WHC17, in Hyderabad, Telangana, India 22 Aug 2017

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Aug 252017

Lifetime achievement award ……..WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA, Award given by Dr. M Sunitha Reddy Head of the Department, Centre for Pharmaceutical Sciences, Institute of Science &Technology, JNTU-H, Kukatpally, Hyderabad, India

Speaking at World health congress 2017….JNTUH Hyderabad 22 aug 2017


Recent progress on fluorination in aqueous media

 Uncategorized  Comments Off on Recent progress on fluorination in aqueous media
Jul 312017

Recent progress on fluorination in aqueous media

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01566F, Tutorial Review
Lian Yang, Tao Dong, Hrishikesh M. Revankar, Cheng-Pan Zhang
Advances of fluorination in aqueous media during the last few decades are summarized in this review

Recent progress on fluorination in aqueous media

*Corresponding authors


Advances in aqueous fluorination during the last few decades are summarized in this review. Fluorinated compounds have dominated a large percentage of agrochemicals and pharmaceuticals and a mass of functional materials. The incorporation of fluorine atoms into organic molecules has become one of the mainstream technologies for their functional modification. Water is very environmentally friendly and has advantageous physicochemical properties. Fluorination reactions in aqueous media are highly sought-after, and have attracted great attention in research areas ranging from medicinal chemistry to materials science. In early times and for a long time, fluorination was thought to be diametrically opposed to water or moisture. However, recent examples have conflicted with this viewpoint. The successful merger of “untamed” fluorine and “mild” water in chemical reactions has set up a new prospect for green chemistry. A considerable amount of remarkable research works have been carried out using water as a (co)solvent and/or a reactant for transformations including electrophilic, radical, or nucleophilic fluorination. We hope that this review will serve as a guide to better understand and to further broaden the field of fluorine chemistry in aqueous conditions.


The installation of fluorine atoms into organic and organometallic frameworks can dramatically change their physical, chemical, and biological properties. Organofluorides have entered many fields of science and technology with a tremendous impact on these domains. The development of efficient, selective, and mild methods to build C-F bonds is of great importance, which is highly desirable to keep up with the rapidly growing demand of novel fluorine-containing scaffolds. In early times, most fluorination reactions required harsh conditions and moisture-sensitive, highly toxic, and explosive atomic fluorine transfer agents like fluorine gas, xenon difluoride, hypofluorite, antimonytrifluoride, and diethylaminosulfurtrifluoride. The discovery of stable electrophilic fluorination reagents such as Selectflour and NFSI has remarkably changed the dilemma, which realized a large number of safe, mild, and easily controllable electrophilic and radical fluorination reactions in aqueous media. Although the exact mechanisms are still unclear at present, it does never hamper the green fluorination method development with these reagents. A mass of successful examples have confirmed that the aqueous reaction medias have positive impacts on electrophilic and radical fluorination reactions with using the N-F reagents and in many cases water can also be a nucleophile for the entire conversions.

In addition, water was generally thought to be an unsuitable medium for nucleophilic fluorination because the fluoride ions can be “trapped” in aqueous medias by hydrogen bonding and become unreactive. Thus, their use in organic synthesis has been quite limited to polar aprotic solvents. Although the strong hydrogen bond formed between fluoride and water diminished the nucleophilicity of fluoride ions, the recent examples of nucleophilic fluorination in aqueous media have implied that this “negative” effect does not always harm the reaction. Besides, the radioisotope 18F has been considered to be a good choice for PET imaging owing to its desirable radiochemical properties. With a half-life of 110 minutes, the introduction of [ 18F]fluorine atoms into biomolecules has to be completed in a swift manner to minimize the loss of radioactivity. Nucleophilic incorporation of [18F]F‒ in aqueous conditions could rapidly produce [18F]fluorinesubstituted biomolecules, which avoided azeotropic drying process, shortened the production time, and minimized the loss of activity. We summarized the recent aqueous fluorination reactions in three sections according to their possible mechanisms. The successful amalgamation of “ill-tempered” fluorine and “benign” water has boded well for green fluorine chemistry. Water behaves as a cosolvent to dissolve fluorination reagents and/or as a reactant for bifunctionalization. Since the aspects of green chemistry has drawn much attention from the society, the pursuit of more efficient and milder reaction conditions for greener fluorination in aqueous medias will never end. Although a large number of research works have been published in this area, it’s only the tip of the iceberg with a wide scope for improvement. We hope that this review will serve as a guide to understand and to further broaden the field of aqueous fluorine chemistry. To meet the principle of green chemistry in modern synthesis, the development of new fluorination reagents as well as valid catalytic systems is crucial for mild and selective C-F bond formation. It’s undoubted that a growing number of green fluorination methodologies in aqueous media will be witnessed in the near future.



Ecocatalyzed Suzuki cross coupling of heteroaryl compounds

 spectroscopy, SYNTHESIS  Comments Off on Ecocatalyzed Suzuki cross coupling of heteroaryl compounds
Jul 302017

Ecocatalyzed Suzuki cross coupling of heteroaryl compounds

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01672G, Paper
Guillaume Clave, Franck Pelissier, Stephane Campidelli, Claude Grison
A bio-based EcoPd was developed for the Suzuki cross coupling of heteroaryl compounds.

Ecocatalyzed Suzuki cross coupling of heteroaryl compounds



A bio-based EcoPd was developed for the Suzuki cross coupling of heteroaryl compounds. Based on the ability of Eichhornia crassipes to bioconcentrate Pd in its roots, we addressed the transformation of plant-derived Pd metals to green catalysts. The methodology is based on eco-friendly procedures. It allowed the preparation of a wide range of heterocyclic biaryl and heterocyclic–heterocyclic biaryl compounds, with a low Pd catalyst loading. EcoPd was found to have the ideal microstructure to promote complex Suzuki reactions without ligands or additives. For the first time, post-reaction solution was treated by rhizofiltration. The resulting EcoPd has been reused with the same performance. This work has established the ecocatalysis concept as a powerful strategy for Pd sustainability, with the development of homogeneous catalysts that are easily recycled and reused.

str4 str5 str6

2-Bromothiophene (20 g, 125 mmol), Phenyl boronic acid (16.8 g, 138 mmol), potassium carbonate (20.7 g, 150 mmol) and EcoPd1 (113 mg, 125 µmol of Pd, 13.3 mg of Pd, EcoPd1 at 11.7 wt% of Pd) were suspended into degassed glycerol (200 mL). The mixture was stirred at 120°C for 4h thanks to an oil bath under an argon atmosphere. The reaction was checked for completion by TLC (cyclohexane) and GCMS analysis after a short extraction of the organic material: 10 µL of the crude were added into a 1 mL microtube containing a mixture of water and AcOEt (800 µL, 1:1, v/v) ; the microtube was vortexed before using the organic layer to perform analysis. Deionised water (500 mL) and AcOEt (500 mL) were added into the flask and the mixture filtered through fritted glass to isolate black Pd for recycling. The organic layer was further washed by deionised water (500 mL x 3) before drying over Na2SO4. The organic layer was filtered and concentrated under vacuum. The residue was then purified by chromatography on a silica gel column (250 g) with pure cyclohexane as the mobile phase, giving the desired coupled compound as a white powder (18 g, 112.5 mmol, yield 90%) Rf = 0.7 (cyclohexane).

1H NMR (300 MHz, CDCl3):  = 7.10- 7.13 (m, 2H), 7.44-7.26 (m, 5H), 7.38-7.33 (m, 1H).

13C NMR (75.5 MHz, CDCl3):  = 123.0, 124.8, 125.9, 127.4, 128.0, 128.8, 134.4, 144.4.

MS (EI): m/z = 160 (M+ , 100%), 128 (21%), 115 (54%), 89 (17%) calcd for C10H8S: 159.99.




Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

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Jul 242017

Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry

Med. Chem. Commun., 2017, 8,1378-1392
DOI: 10.1039/C7MD00109F, Review Article
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Alice Coletti, Francesco Antonio Greco, Daniela Dolciami, Emidio Camaioni, Roccaldo Sardella, Maria Teresa Pallotta, Claudia Volpi, Ciriana Orabona, Ursula Grohmann, Antonio Macchiarulo
Structure-function relationships of IDO1 and structure-activity relationships of inhibitors are discussed with an outlook on next generation IDO1 ligand.


Advances in indoleamine 2,3-dioxygenase 1 medicinal chemist

 Author affiliations


Indoleamine 2,3-dioxygenase 1 (IDO1) mediates multiple immunoregulatory processes including the induction of regulatory T cell differentiation and activation, suppression of T cell immune responses and inhibition of dendritic cell function, which impair immune recognition of cancer cells and promote tumor growth. On this basis, this enzyme is widely recognized as a valuable drug target for the development of immunotherapeutic small molecules in oncology. Although medicinal chemistry has made a substantial contribution to the discovery of numerous chemical classes of potent IDO1 inhibitors in the past 20 years, only very few compounds have progressed in clinical trials. In this review, we provide an overview of the current understanding of structure–function relationships of the enzyme, and discuss structure–activity relationships of selected classes of inhibitors that have shaped the hitherto few successes of IDO1 medicinal chemistry. An outlook opinion is also given on trends in the design of next generation inhibitors of the enzyme.

Introduction Indoleamine 2,3-dioxygenases (IDOs) are heme-containing proteins that catalyze the oxidative cleavage of the indole ring of tryptophan (L-Trp, 1) to produce N-formyl kynurenine (2) in the first rate limiting step of the kynurenine pathway (Figure 1).1,2 The family includes two related enzymatic isoforms, namely IDO1 and IDO2, sharing ∼60% of sequence similarity and featuring distinct biochemical features.3,4 A third enzyme of the family is the tryptophan-2,3-dioxygenase (TDO2) which is structurally unrelated to IDO1 and IDO2 and is endowed with a more stringent substrate specificity for L-Trp.5 Although TDO2 is expressed almost exclusively in hepatocytes where it regulates L-Trp catabolism in response to the diet, IDO1 and IDO2 are widely expressed in macrophages and dendritic cells exerting immunoregulatory functions.6 These are accomplished through two major mechanisms including depletion of tryptophan and production of bioactive metabolites along the kynurenine pathway. Specifically, the first mechanism postulates that raising levels of Interferon-γ (IFN-γ) induce IDO1 expression in macrophages and dendritic cells during pathogen infection, leading to consumption of L-Trp and growth arrest of pathogens, whose diet is sensitive to this essential nutrient.7 The second mechanism grounds on production of kynurenine metabolites that bind to the aryl hydrocarbon receptor (AhR), activating signaling pathways that enhance immune tolerance.8-10 Among the three proteins, IDO1 is the most characterized enzyme and in recent years a second signal-transducing function was revealed for this protein.11,12 In particular, this signalling function relies on the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the non-catalytic domain of IDO1.13 The immunosuppressive cytokine transforming growth factor-β (TGF-β) stimulates phosphorylation of ITIMs by Sarcoma-family (Src-family) kinases and consequent interaction of the phosphorylated enzyme with Src Homology 2 domain Phosphatase-1 (SHP-1) and Src Homology 2 domain Phosphatase-2 (SHP-2), eventually leading to long-term expression of IDO1 and immune tolerance. Conversely, in pro-inflammatory environmental conditions, increasing levels of interleukin-6 (IL-6) trigger the interaction of

phosphorylated IDO1 with suppressor of cytokine signalling 3 (SOCS3) that tags the enzyme for proteasome degradation, shortening IDO1’s half-life and promoting inflammatory response.14 The breakthrough discovery that IDO1 plays a crucial role in the maintenance of maternal immune tolerance ushered in a great deal of interest on the enzyme, by then considered a master regulatory hub of immunosuppressive pathways in pregnancy, autoimmune diseases, chronic inflammation, and cancer.15 In this framework, elevated levels of IDO1 expression found in several tumour cells were associated to the participation of the enzyme in the tumor immuno-editing process which sets up immune tolerance to tumor antigens.16,17 On this basis, academic groups and pharmaceutical companies have been engaged in the development of IDO1 inhibitors.18 Although part of these efforts has proved successful, with a large array of potent and selective inhibitors being disclosed in literature and patent applications, only few compounds have hitherto entered clinical trials (3-7, Figure 1).2,19-22 At this regard, some studies have highlighted challenges in the development of enzyme inhibitors mostly due to redox properties of the enzyme that may account for unspecific mechanism of inhibition of many compounds discovered in preclinical studies.23,24 Starting with an overview on the architecture of IDO1 and its structure-function relationships, in this article we discuss selected classes of inhibitors that have shaped advances in the medicinal chemistry of IDO1, providing outlooks on future trends in the design of next generation compounds.


Antonio Macchiarulo

Antonio Macchiarulo


Francesco Antonio Greco

Francesco Antonio Greco



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