Synthesis and antimycobacterial evaluation of new 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives

  • Vikas Shinde
  • Pramod MahulikarEmail author
  • Pravin C. MhaskeEmail author
  • Shakti Chakraborty
  • Amit Choudhari
  • Siddharth Phalle
  • Prafulla Choudhari
  • Dhiman Sarkar
Original Research


A new series of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methyl-2-arylthiazole derivatives, 6aw have been synthesized by click reaction of substituted benzylazide, 5a−d with 5-ethynyl-4-methyl-2-substituted phenylthiazole, 4af. The starting compounds 4-ethynyl-2-substituted phenylthiazole (4a−f) were synthesized from the corresponding thiazole aldehyde by using the Ohira−Bestmann reagent. The structure of the synthesized compounds was determined by spectral analysis. All the synthesized compounds were screened for their preliminary antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB, ATCC 25177). Most of the synthesized compounds reported good activity against M. tuberculosis H37Ra strain with IC50 range of 0.58−8.23 µg/mL. Compounds 6g and 6k reported good antitubercular activity with MIC90 values of 4.71 and 2.22 µg/mL, respectively. Potential antimycobacterial activity suggested that these compounds could serve as good lead compounds for further optimization and development of a newer antitubercular candidate.


Thiazole 1,2,3-Triazole Ohira−Bestmann reagent Antitubercular activity Molecular docking 



The authors would like to thank CSIR-NCL, Pune for supporting the biological activity. Central Analysis facility, Savitribai Phule Pune University, Pune is also acknowledged for the spectral analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abhale YK, Sasane AV, Chavan AP, Deshmukh KK, Kotapalli SS, Ummanni R, Sayyad SF, Mhaske PC (2015) Synthesis and biological screening of 20-aryl/benzyl-2-aryl-4-methyl-4,5-bithiazolyls as possible anti-tubercular and antimicrobial agents. Eur J Med Chem 94:340Google Scholar
  2. Abhale YK, Deshmukh KK, Sasane AV, Chavan AP, Mhaske PC (2016) Synthesis and antitubercular activity of novel 6-substituted-2-(4-methyl-2-substituted phenylthiazol-5-yl)H-imidazo[1,2-a]pyridine. J Heterocycl Chem 53:229Google Scholar
  3. Abhale YK, Sasane AV, Chavan AP, Shekh SH, Deshmukh KK, Bhansali S, Nawale L, Sarkar D, Mhaske PC (2017) Synthesis and antimycobacterial screening of new thiazolyl-oxazole derivatives. Eur J Med Chem 132:333Google Scholar
  4. Alley MC, Scudiere DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48(3):589–601Google Scholar
  5. Azzali E, Machado D, Kaushik A, Vacondio F, Flisi S, Cabassi C, Lamichhane G, Viveiros M, Costantino G, Pieroni M (2017) Substituted N-phenyl-5-(2-(phenylamino)thiazol-4-yl)isoxazole-3-carboxamides are valuable antitubercular candidates that evade innate efflux machinery. J Med Chem 60:7108Google Scholar
  6. Bansode P, Jadhav J, Kurane R, Choudhari P, Bhatia M, Khanapure S, Salunkhe R, Rashinkar G (2016) Potentially antibreast cancer enamidines via azide– alkyne–amine coupling and their molecular docking studies. RSC Adv 6:90597Google Scholar
  7. Barradas JS, Errea MI, D’Accorso NB, Sepulveda CS, Damonte EB (2011) Imidazo[2,1-b]thiazole carbohydrate derivatives: Synthesis and antiviral activity against Junin virus, agent of Argentine hemorrhagic fever. Eur J Med Chem 46:259–264Google Scholar
  8. Chen MD, Lu SJ, Yuag GP, Yang SY, Du XL (2000) Synthesis and antibacterial activity of some heterocyclic beta-enamino ester derivatives with 1, 2, 3-triazole. Heterocycl Comm 6:421Google Scholar
  9. Christian F, Ben M, Susan Z, Joey M, Hua Z, Colby BW (2008) Preparation of triazole derivatives for treating Alzheimer’s disease and related conditions, WIPO patent, WO2008156580A1Google Scholar
  10. Davyt D, Serra G (2010) Thiazole and oxazole alkaloids: isolation and synthesis. Mar Drugs 8:2755Google Scholar
  11. Dmitry V, Demchuk AV, Samet NB, Chernysheva VI, Ushkarov GA, Stashina LD, Konyushkin MM, Raihstat SI, Firgang AA, Philchenkov MP, Zavelevich LM, Kuiava VF, Chekhun DY, Blokhin AS, Kiselyov MN, Semenova VV (2014) Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines. Bioorg Med Chem 22:738Google Scholar
  12. Dongamanti A, Arram G, Bommidi V, Sidda R, Banoth R (2014) Microwave assisted synthesis and antimicrobial activity of novel 1-[1/2-(1-Benzyl-1H-[1,2,3]triazol-4-ylmethoxy)-naphthalen-2/1-yl]-3-(1-phenyl-3-aryl-1H-pyrazol-4-yl)-propenones. Org Commun 8:24Google Scholar
  13. Farghaly A. R, El-Kashef H (2006) Synthesis of some new azoles with antiviral potential ARKIVOC xi_76Google Scholar
  14. Foks H, Janowiec M, Zwolska Z, Augustynowicz-Kopeć E (2005) Synthesis and tuberculostatic activity of some 2-Piperazinmethylene derivatives 1,2,4-Triazole-3-Thiones. Phosphorus Sulfur Silicon Relat Elem 180:537Google Scholar
  15. Gaikwad ND, Patil SV, Bobade VD (2012a) Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives. Bioorg & Med Chem Lett 22:3449Google Scholar
  16. Gaikwad ND, Patil SV, Bobade VD (2012b) Hybrids of ravuconazole: Synthesis and biological evaluation. Eur J Med Chem 54:295Google Scholar
  17. Giri RS, Thaker HM, Giordano T, Williams J, Rogers D, Sudersanam V, Vasu KK (2009) Synthesis and characterization of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-kB and AP-1 mediated transcription activation and as potential anti-inflammatory agents. Eur J Med Chem 44:2184Google Scholar
  18. Gonzaga DT, da Rocha DR, da Silva FC, Ferreira VF (2013) Recent advances in the synthesis of new antimycobacterial agents based on the 1H-1,2,3-triazoles. Curr Top Med Chem 13:2850Google Scholar
  19. Guan LP, Jin QH, Tian GR, Chai KY, Quan ZS (2007) Synthesis of some quinoline-2(1H)-one and 1,2,4-triazolo [4,3-a]quinoline derivatives as potent anticonvulsants. J Pharm Sci 10:254Google Scholar
  20. Gujjar R, Marwaha A, White J, White L, Creason S, Shackleford DM, Baldwin J, Charman WN, Buckner FS, Charman S, Rathod PK, Phillips MA (2009) Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem 52:1864Google Scholar
  21. Güzeldemirci NU, Küçükbasmac Ö (2010) Synthesis and antimicrobial activity evaluation of new 1,2,4-triazoles and 1,3,4-thiadiazoles bearing imidazo[2,1-b]thiazole moiety. Eur J Med Chem 45:63Google Scholar
  22. Hafez HN, Abbas HA, El-Gazzar AR (2008) Synthesis and evaluation of analgesic, anti-inflammatory and ulcerogenic activities of some triazolo- and 2-pyrazolyl-pyrido[2,3-d]-pyrimidines. Acta Pharm 58:359Google Scholar
  23. Holla BS, Mahalinga M, Karthikeyen MS, Poojary B, Akberali PM, Kumari NS (2005) Synthesis, characterization and antimicrobial activity of some substituted 1,2,3-triazoles. Eur J Med Chem 40:1173Google Scholar
  24. Jadhav GR, Shaikh MU, Kale RP, Shiradkar MR, Gill CH (2009) SAR study of clubbed [1,2,4]-triazolyl with fluorobenzimidazoles as antimicrobial and antituberculosis agents. Eur J Med Chem 44:2930Google Scholar
  25. Jeankumar VU, Chandran M, Samala G, Alvala M, Koushik PV, Yogeeswari P, Salina EG, Sriram D (2012) Development of 5-nitrothiazole derivatives: Identification of leads against both replicative and latent Mycobacterium tuberculosis. Bioorg & Med Chem Lett 22:7414Google Scholar
  26. Jeankumar VU, Rudraraju SR, Vats R, Janupally R, Saxena S, Yogeeswari P, Sriram D (2016) Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors. Eur J Med Chem 122:216Google Scholar
  27. Jeong K, Lee J, Park S, Choi J, Jeong D, Choi D, Nam Y, Park J, Lee K, Kim S, Ku J (2015) Synthesis and in-vitro evaluation of 2-amino-4-arylthiazole as inhibitor of 3D polymerase against foot-and-mouth disease (FMD). Eur J Med Chem 102:375Google Scholar
  28. iLOGP (2014) a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J Chem Inf Model 54:3284Google Scholar
  29. Karale BK, Takate SJ, Salve SP, Zaware BH, Jadhav SS (2014) Synthesis and biological screening of thiazolyl triazoles and thiazoles. Indian J Chem 53B:339Google Scholar
  30. Kashyap SJ, Garg VK, Sharma PK, Kumar N, Dudhe R, Gupta JK (2012) Thiazoles: having diverse biological activities. Med Chem Res 21:2123Google Scholar
  31. Kathiravan MK, Salake A, Chothe AS, Dudhe PB, Watode RP, Mukta MS, Gadhwe S (2012) The biology and chemistry of antifungal agents: a review. Bioorg & Med Chem 20:5678Google Scholar
  32. Keri RS, Patil SA, Budagumpi S, M.Nagaraja B (2015) Triazole: a promising antitubercular agent. Chem Biol Drug Des 86:410Google Scholar
  33. Khan A, Sarkar D (2008) A simple whole cell based high throughput screening protocol using Mycobacterium bovis BCG for inhibitors against dormant and active tubercle bacilli. J Microbiol Methods 73:62Google Scholar
  34. Kouatly O, Geronikaki A, Kamoutsis C, Hadjipavlou-Litina D, Eleftheriou P (2008) Adamantane derivatives of thiazolyl-N-substituted amide, as possible non-steroidal anti-inflammatory agents. Eur J Med Chem 44:1198Google Scholar
  35. Krishna KM, Inturi B, Pujar GV, Purohit MN, Vijaykumar GS (2014) Design, synthesis and 3D-QSAR studies of new diphenylamine containing 1,2,4-triazoles as potential antitubercular agents. Eur J Med Chem 84:516Google Scholar
  36. Li H, He D, Zhao X, Sun T, Zhang Q, Bai C, Chen Y (2018) Design and synthesis of novel dasatinib derivatives as inhibitors of leukemia stem cells. Bio-Org Med Chem Lett 28:700Google Scholar
  37. Liu ZY, Wang YM, Li ZR, Jiang JD, Boykin DW (2009) Synthesis and anticancer activity of novel 3,4-diarylthiazol-2(3H)-ones (imines). Bioorg Med Chem 19:5661Google Scholar
  38. Liu Z, Zhu Q, Li F, Zhang L, Leng Y, Zhang A (2011) N-(5-substituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators. Med Chem Commun 2:531Google Scholar
  39. Martinelli LKB, Rotta M, Villela AD, Rodrigues-Junior VS, Abbadi BL, Trindade RV, Petersen GO, Danesi GM, Nery LR, Pauli I, Campos MM, Bonan CD, de Souza ON, Basso LA, Santos DS (2017) Functional, thermodynamics, structural and biological studies of in silico-identified inhibitors of Mycobacterium tuberculosis enoyl-ACP(CoA) reductase enzyme. Sci Rep 7:46696Google Scholar
  40. Mishra CB, Kumari S, Tiwari M (2015) Thiazole: A promising heterocycle for the development of potent CNS active agents. Eur J Med Chem 92:1Google Scholar
  41. Oniga O, Ndongo JT, Moldovan C, Tiperciuc B, Oniga S, Pirnau A, Vlase L, Verite P (2012) Synthesis and antimicrobial activity of some new 2- hydrazone-thiazoline-4-ones. Farmacia 60:6785Google Scholar
  42. Oniga S, Duma M, Oniga O, Tiperciuc B, Pirnau A, Araniciu C, Palage M (2015) Synthesis of some new 4-methyl-2-(4-pyridyl)-thiazole-5-yl-azoles as potential antimicrobial agents. Farmacia 63:2Google Scholar
  43. Pandya DH, Sharma JA, Jalani HB, Pandya AN, Sudarsanam V, Kachler S, NorbertKlotz K, Vasu KK (2015) Novel thiazole–thiophene conjugates as adenosine receptor antagonists: Synthesis, biological evaluation and docking studies. Bioorg & Med Chem Lett 25:1306Google Scholar
  44. Passannanti A, Diana P, Barraja P, Mingooia F, Lauria A, Cirrincine G (1998) Pyrrolo[2,3-d][1,2,3]triazoles as potential antineoplastic agents. Heterocycles 48:1229Google Scholar
  45. Patil KT, Walekar LS, Undare SS, Kolekar GB, Deshmukh MB, Choudhari PB, Anbhule PV (2016) Selective synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione using copper oxide nanoparticles for potential inhibitors of β-ketoacyl-[acyl-carrier-protein]synthase III of Mycobacterium tuberculosis. Indian J Chem Sect B 55B:1151Google Scholar
  46. Patpi SR, Pulipati L, Yogeeswari P, Sriram D, Jain N, Sridhar B, Murthy R, Devi AT, Kalivendi SV, Kantevari S (2012) Design, synthesis, and structure–activity correlations of novel dibenzo[b,d]furan, dibenzo[b,d]thiophene, and N-methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of Mycobacterium tuberculosis. J Med Chem 55:3911Google Scholar
  47. Patravale AA, Gore AH, Kolekar GB, Deshmukh MB, Choudhari PB, Bhatia MS, Prabhu S, Jamdhade MD, Patole MS, Anbhule PV (2016) Synthesis, biological evaluation and molecular docking studies of some novel indenospiro derivatives as anticancer agents. J Taiwan Inst Chem Eng 68:105Google Scholar
  48. Ramesh R, Shingare RD, Kumar V, Anand A, Swetha B, Veeraraghavan S, Viswanadha S, Ummanni R, Gokhale R, Reddy DS (2016) Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents. Eur J Med Chem 122:723Google Scholar
  49. Reddy T, Kulhari H, Reddy V, Rao AVS, Bansal V, Kamal A, Shukla R (2015) Synthesis and biological evaluation of pyrazolo-triazole hybrids as cytotoxic and apoptosis inducing agents. Organic & Biomol Chem 13:10136Google Scholar
  50. Rostom SAF, El-Ashmawy IM, Abd El Razik HA, Badr MH, Ashour HMA (2009) Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents. Bioorg Med Chem 17:882Google Scholar
  51. Samala G, Devi PB, Saxena S, Meda N, Yogeeswari P, Sriram D (2016) Design, synthesis and biological evaluation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole derivatives as Mycobacterium tuberculosis pantothenate synthetase inhibitors. Bioorg & Med Chem 24:1298Google Scholar
  52. Sarkar S, Sarkar D (2012) Potential use of nitrate reductase as a biomarker for the identification of active and dormant inhibitors of Mycobacterium tuberculosis in a THP1 infection model. J Biomol Screen 17:966Google Scholar
  53. Shaikh MH, Subhedar DD, Nawale L, Sarkar D, Khan FAK, Sangshetti JN, Shingate BB (2015) 1,2,3-Triazole derivatives as antitubercular agents: synthesis, biological evaluation and molecular docking study. Med Chem Comm 6:1104Google Scholar
  54. Shanmugavelan P, Nagarajan S, Sathishkumar M, Ponnuswamy A, Yogeeswari P, Sriram D (2011) Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis. Bioorg Med Chem Lett 21:7273Google Scholar
  55. Shanthi V, Ramanathan K (2014) Identification of potential inhibitor targeting enoyl-acyl carrier protein reductase (InhA) in Mycobacterium tuberculosis: a computational approach. Biotech 4:253Google Scholar
  56. Shelke SH, Mhaske PC, Nandave M, Narkhade S, Walhekar NM, Bobade VD (2012) Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl) thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents. Bioorg Med Chem Lett 22:6373Google Scholar
  57. Shinde V, Mahulikar P, Mhaske PC, Nawale L, Sarkar D (2018) Synthesis and biological evaluation of new 2-aryl-4-((4-aryl-1H-1,2,3-triazol-1-yl)methyl)thiazole derivatives. Res Chem Intermed 44:1247Google Scholar
  58. Shiradkar M, Kumar S, Dasari V, Tatikonda S, Akula KC, Shah R (2007) Clubbed triazoles: a novel approach to antitubercular drugs. Eur J Med Chem 42:807Google Scholar
  59. Shiradkar MR, Murahari KK, Reddy GH, Tatikonda S, Chakravarthy AK, Dolly P, Kaur R, Burange P, Ghogare J, Mokalec V, Rautc M (2007) Synthesis of new S-derivatives of clubbed triazolyl thiazole as anti-Mycobacterium tuberculosis agents. Bioorg Med Chem 15:3997Google Scholar
  60. Shiran JA, Yahyazadeh A, Mamaghani M, Rassa M (2013) Regioselective synthesis of novel 3-allyl-2-(substituted imino)-4-phenyl-3H-thiazole and 2,2′-(1,3-phenylene)bis(3-substituted-2-imino-4-phenyl-3H-thiazole) derivatives as antibacterial agents. J Mol Struct 1039:113Google Scholar
  61. Shenoi S, Friedland G (2009) Extensively drug-resistant tuberculosis: a new face to an old pathogen. Annu Rev Med 60:307Google Scholar
  62. Shirude PS, Madhavapeddi P, Naik M, Murugan K, Shinde V, Nandishaiah R, Bhat J, Kumar A, Hameed S, Holdgate G, Davies G, McMiken H, Hegde N, Ambady A, Venkatraman J, Panda M, Bandodkar B, Sambandamurthy VK, Read JA (2013) Methyl-Thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in mycobacterium tuberculosis. J Med Chem 56:8533Google Scholar
  63. Singh R, Nawale L, Arkile M, Shedbalkar U, Wadhwani S, Sarkar D, Chopade B (2015) Chemical and biological metal nanoparticles as antimycobacterialagents: a comparative study. Int J Antimicrob Agents 46:183Google Scholar
  64. Skedelj V, Perdih A, Brvar M, Kroflic A, Dubbée V, Savage V, O’Neill AJ, Solmajer T, Bester-Rogac M, Blanot D, Hugonnet JE, Magnet S, Arthur M, Mainardi JL, Stojan J, Zega A (2013) Discovery of the first inhibitors of bacterial enzyme d-aspartate ligase from Enterococcus faecium (Aslfm). Eur J Med Chem 67:208Google Scholar
  65. SwissADME (2017) a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717Google Scholar
  66. Tantry SJ, Markad SD, Shinde V, Bhat J, Balakrishnan G, Gupta AK, Ambady A, Raichurkar A, Kedari C, Sharma S, Mudugal NV, Narayan A, Naveen Kumar CN, Nanduri R, Bharath S, Reddy J, Panduga V, Prabhakar KR, Kandaswamy K, Saralaya R, Kaur P, Dinesh N, Guptha S, Rich K, Murray D, Plant H, Preston M, Ashton H, Plant D, Walsh J, Alcock P, Naylor K, Collier M, Whiteaker J, McLaughlin RE, Mallya M, Panda M, Rudrapatna S, Ramachandran V, Shandil R, Sambandamurthy VK, Mdluli K, Cooper CB, Rubin H, Yano T, Iyer P, Narayanan S, Kavanagh S, Mukherjee K, Balasubramanian V, Hosagrahara VP, Solapure S, Ravishankar S, Shahul HP (2017) Discovery of Imidazo[1,2-a]pyridine ethers and squaramides as selective and potent inhibitors of mycobacterial adenosine triphosphate (ATP) synthesis. J Med Chem 60:1379Google Scholar
  67. Tomasic T, Katsamakas S, Hodnik Z, Ilas J, Brvar M, Solmajer T, Montalvao S, Tammela P, Banjanac M, Ergovic G, Anderluh M, Masic LP, Kikelj D (2015) Discovery of 4,5,6,7-Tetrahydrobenzo [1,2-d]thiazoles as novel DNA gyrase inhibitors targeting the ATP-binding site. J Med Chem 58:5501Google Scholar
  68. Wang Q, Song F, Xiao X, Huang P, Li L, Monte A, Abdel-Mageed WM, Wang J, Guo H, He W, Xie F, Dai H, Liu M, Chen C, Xu H, Liu M, Piggott AM, Liu X, Capon RJ, Zhang L (2013) Abyssomicins from the South China Sea deep-sea sediment Verrucosispora sp.: natural thioether Michael addition adducts as antitubercular prodrugs. Angew Chem Int Ed 52:1231Google Scholar
  69. Wang X, Dai Z, Chen Y, Cao L, Yan W, Li S, Wang J, Zhang Z, Ye Y (2017) Synthesis of 1,2,3-triazole hydrazide derivatives exhibiting anti-phytopathogenic activity. Eur J Med Chem 126:171Google Scholar
  70. Weide T, Saldanha SA, Minond D, Spicer TP, Fotsing JR, Spaargaren M, Frere J, Bebrone C, Sharpless KB, Hodder PS, Fokin VV (2010) NH-1,2,3-Triazole inhibitors of the VIM-2 metallo-β-lactamase. ACS Med Chem Lett 1:150Google Scholar
  71. World Health Organization (2016) Tuberculosis Fact Sheet.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vikas Shinde
    • 1
  • Pramod Mahulikar
    • 1
    Email author
  • Pravin C. Mhaske
    • 2
    Email author
  • Shakti Chakraborty
    • 3
  • Amit Choudhari
    • 3
  • Siddharth Phalle
    • 4
  • Prafulla Choudhari
    • 4
  • Dhiman Sarkar
    • 3
  1. 1.School of Chemical SciencesNorth Maharashtra UniversityJalgaonIndia
  2. 2.Post Graduate Department of Chemistry, S.P. Mandali’s Sir Parashurambhau CollegeSavitribai Phule Pune UniversityPuneIndia
  3. 3.CombiChemBio Resource CentreCSIR-National Chemical LaboratoryPuneIndia
  4. 4.Department of Pharmaceutical ChemistryBharati Vidyapeeth College of PharmacyKolhapurIndia

Personalised recommendations