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Anti-Infective Agents

Author(s): Narender Malothu, Malathi Jojula, Venkat Rao Kaki, Raghuram Reddy Adidala and Raghuram Rao Akkinepally*

DOI: 10.2174/2211352520666220317141315

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Synthesis, In vitro Antibacterial and Antimycobacterial Activity and Docking Study of Thieno(3,2-e)(1,2,4)triazolo(1,5-c)pyrimidines

Article ID: e170322202323 Pages: 10

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Abstract

Background: Emergence of drug resistance and severe side effects with current antitubercular drugs urges the development of more efficacious and safer new agents. The present study focused on this direction to develop new hetero-fused pyrimidines as potential antitubercular agents.

Objective: The objective of the study was to synthesize and assess the antibacterial and antimycobacterial activity of novel 1,2,4-triazole ring bearing hetero-fused thienopyrimidines (6a-j & 7a-j). Also to evaluate the binding pattern of synthesized molecules at the target site and study their ADME properties by in silico tools.

Methods: Two series of hetero fused thienopyrimidines (6a-j & 7a-j) were synthesized and tested for their antibacterial potentiality against B. subtilis, S. aureus, E. coli, and K. pneumonia. Compounds with potential antibacterial activity were further tested for their antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid (INH)-resistant clinical sample of MTB using broth microdilution method. The binding efficacy at the enzyme site was evaluated by the molecular docking study using pantothenate synthetase (MTB-PS) (PDB: 3IVX) as the target protein. Further, in silico ADME properties of title compounds were explored by Swiss ADME online tools.

Results: In this study, few compounds were found promising in exhibiting potent inhibitory activity against E. coli and MTB. Among these compounds, 6h (MTB: MIC-17.13±0.88 μM) and 6i (MTB: MIC-17.55±0.72 μM) displayed significant antimycobacterial activity. The molecular docking results suggested the efficient binding of biologically potential molecules.

Conclusion: Compounds bearing N-benzyl moiety at the core nucleus with a p-nitro aryl side chain (6h) exhibited significant antitubercular activity. In silico studies showed effective binding at the target site and also indicated good compatibility in ADME properties.

Keywords: Triazolo(1, 5-c)pyrimidine, antimycobacterial activity, INH-resistant, pantothenate synthetase, M. tuberculosis H37Rv¸ antitubercular drugs.

Graphical Abstract

[1]
WHO Global tuberculosis report. , 2019. Available from:http://www.who.int/tb/publications
[2]
Gualano, G.; Capone, S.; Matteelli, A.; Palmieri, F. New antituberculosis drugs: From clinical trial to programmatic use. Infect. Dis. Rep., 2016, 8(2), 6569.
[http://dx.doi.org/10.4081/idr.2016.6569] [PMID: 27403268]
[3]
Szumowski, J.D.; Lynch, J.B. Profile of delamanid for the treatment of multidrug-resistant tuberculosis. Drug Des. Devel. Ther., 2015, 9, 677-682.
[PMID: 25678771]
[4]
Shetty, N.S.; Lamani, R.S.; Khazi, I.A. Synthesis and antimicrobial activity of some novel thienopyrimidines and triazolothieno-pyrimidines. J. Chem. Sci., 2009, 121(3), 301-307.
[http://dx.doi.org/10.1007/s12039-009-0034-7]
[5]
Shetty, N.S.; Gaonkar, S.L.; Pai, V.V.; Manvith, S.K. Synthesis and antimicrobial activity of tricyclic thienopyrimidines and 1, 3, 4-Triazole fused thienopyrimidines. J. Chem. Sci. Tech., 2011, 2(1), 10-13.
[6]
Al-Taisan, K.M.; Al-Hazimi, H.M.A.; Al-Shihry, S.S. Synthesis, characterization and biological studies of some novel thieno[2,3-d]pyrimidines. Molecules, 2010, 15(6), 3932-3957.
[http://dx.doi.org/10.3390/molecules15063932] [PMID: 20657418]
[7]
Aly, A.; El-Karim, I.A. Facile synthesis of new pyrazolopyrimidine derivatives of potential biosignificant interest. J. Kor. Chem. Soc., 2011, 55(5), 781-786.
[http://dx.doi.org/10.5012/jkcs.2011.55.5.781]
[8]
Chaudhary, M.; Bhattacharya, S.; Ahmad, Y. Design and synthesis of quinazolinone derivatives as a novel antitubercular agents. Der. Pharm. Lett., 2012, 4, 954-960.
[9]
Luo, Y.; Zhang, S.; Liu, Z.J.; Chen, W.; Fu, J.; Zeng, Q.F.; Zhu, H.L. Synthesis and antimicrobical evaluation of a novel class of 1,3,4-thiadiazole: Derivatives bearing 1,2,4-triazolo[1,5-a]pyrimidine moiety. Eur. J. Med. Chem., 2013, 64, 54-61.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.014] [PMID: 23644188]
[10]
Patil, V.; Kale, M.; Raichurkar, A.; Bhaskar, B.; Prahlad, D.; Balganesh, M.; Nandan, S.; Shahul Hameed, P. Design and synthesis of triazolopyrimidine acylsulfonamides as novel anti-mycobacterial leads acting through inhibition of acetohydroxyacid synthase. Bioorg. Med. Chem. Lett., 2014, 24(9), 2222-2225.
[http://dx.doi.org/10.1016/j.bmcl.2014.02.054] [PMID: 24703230]
[11]
Narender, M.; Jaswanth, S. B.; Umasankar, K.; Malathi, J.; Raghuram Reddy, A.; Umadevi, K.R.; Dusthackeer, A.V.N.; Venkat Rao, K.; Raghuram R, A. Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido [4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases. Bioorg. Med. Chem. Lett., 2016, 26(3), 836-840.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.083] [PMID: 26755393]
[12]
Malothu, N.; Kulandaivelu, U.; Jojula, M.; Gunda, S.K.; Akkinepally, R.R. Synthesis, antimycobacterial evaluation and docking studies of some 7-methyl-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3h)-ones. Chem. Pharm. Bull. , 2018, 66(10), 923-931.
[http://dx.doi.org/10.1248/cpb.c17-00999] [PMID: 30270239]
[13]
Jorgensen, J.H.; Ferraro, M.J. Antimicrobial susceptibility testing: A review of general principles and contemporary practices. Clin. Infect. Dis., 2009, 49(11), 1749-1755.
[http://dx.doi.org/10.1086/647952] [PMID: 19857164]
[14]
Dewal, M.B.; Wani, A.S.; Vidaillac, C.; Oupický, D.; Rybak, M.J.; Firestine, S.M. Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents. Eur. J. Med. Chem., 2012, 51, 145-153.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.035] [PMID: 22405289]
[15]
Maddali, N.K.; Viswanath, I.V.; Murthy, Y.L.; Bera, R.; Takhi, M.; Rao, N.S.; Gudla, V. Design, synthesis and molecular docking studies of quinazolin-4-ones linked to 1,2,3-triazol hybrids as Mycobacterium tuberculosis H37Rv inhibitors besides antimicrobial activity. Med. Chem. Res., 2019, 28(4), 559-570.
[http://dx.doi.org/10.1007/s00044-019-02313-9]
[16]
Gewald, K.; Schinke, E.; Bottcher, H. 2-Amino-thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Schwefel. Chem. Ber., 1966, 99, 94-100.
[http://dx.doi.org/10.1002/cber.19660990116]
[17]
Puterova, Z.; Krutosikova, A.; Vegh, D. Gewald reaction: Synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC, 2010, 1(1), 209-246.
[http://dx.doi.org/10.3998/ark.5550190.0011.105]
[18]
Aurelio, L.; Valant, C.; Figler, H.; Flynn, B.L.; Linden, J.; Sexton, P.M.; Christopoulos, A.; Scammells, P.J. 3- and 6-Substituted 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridines as A1 adenosine receptor allosteric modulators and antagonists. Bioorg. Med. Chem., 2009, 17(20), 7353-7361.
[http://dx.doi.org/10.1016/j.bmc.2009.08.024] [PMID: 19751980]
[19]
Boyapati, S.; Kulandaivelu, U.; Sangu, S.; Vanga, M.R. Synthesis, antimicrobial evaluation, and docking studies of novel 4-substituted quinazoline derivatives as DNA-gyrase inhibitors. Arch. Pharm., 2010, 343(10), 570-576.
[http://dx.doi.org/10.1002/ardp.201000065] [PMID: 20941729]