Heterocycles in the Treatment of Neglected Tropical Diseases

Kush    K.    Maheshwari; Debasish       Bandyopadhyay

doi:10.2174/0929867327666200219141652

Abstract

Background: Neglected Tropical Diseases (NTDs) affect a huge population of the world and the majority of the victims belong to the poor community of the developing countries. Until now, the World Health Organization (WHO) has identified 20 tropical diseases as NTDs that must be addressed with high priority. However, many heterocyclic scaffolds have demonstrated potent therapeutic activity against several NTDs.

Objective: There are three major objectives: (1) To discuss the causes, symptoms, and current status of all the 20 NTDs; (2) To explore the available heterocyclic drugs, as well as their mechanisms of action (if known), that are being used to treat NTDs; (3) To develop general awareness on NTDs among the medicinal/health research community and beyond.

Methods: The 20 NTDs have been discussed according to their alphabetic orders along with the possible heterocyclic remedies. The current status of treatment with an emphasis on the heterocyclic drugs (commercially available and investigational) has been outlined. In addition, a brief discussion of the impacts of NTDs on socio-economic conditions is included.

Results: NTDs are often difficult to diagnose and the problem is worsened by the unhealthy hygiene, improper awareness, and inadequate healthcare in the developing countries where these diseases primarily affect poor people. The statistics include the duration of suffering, the number of individuals affected, and access to healthcare and medication. The mechanisms of action of various heterocyclic drugs, if reported, have been briefly summarized.

Conclusion: Scientists and pharmaceutical corporations should allocate more resources to reveal the in-depth mechanism of action of many heterocyclic drugs that are currently being used for the treatment of NTDs. Analysis of current heterocyclic compounds and the development of new medications can help in the fight to reduce/remove the devastating effects of NTDs. An opinion-based concise review has been presented. Based on the available literature, this is the first attempt to present all the 20 NTDs and related heterocyclic compounds under the same umbrella.

Keywords: Neglected tropical diseases (NTDs), bacterial, viral, heterocycles, heterocyclic drug, parasite, infection, infestation.

« Previous Next »

[1] 
World Health Organization. Neglected Tropical Diseases, 2019. Available at: https://www.who.int/neglected_ diseases/mediacentre/factsheet/en/ (Accessed: 26 November, 2020).
[2] 
Bandyopadhyay, D.; Banik, B.K. Microwave-induced synthesis of heterocycles of medicinal interests.In: Green Synthetic Approaches for Biologically Relevant Heterocycles; , 2015, 1, pp. 517-557.
[http://dx.doi.org/10.1016/B978-0-12-800070-0.00019-0] 
[3] 
World Health Organization. Buruli ulcer (Mycobacterium ulcerans infection) 2019. Available at: https://www. who.int/en/news-room/fact-sheets/detail/buruli-ulcer-(myco -bacterium-ulcerans-infection) (Accessed: 26 November, 2020).
[4] 
Vadim, M.; Stewart, C. 2-piperazin-1-yl-4h-1,3-benzothiazin-4-one derivatives and their use for the treatment of mammalian infections. WO Patent (A1) 2,012,066,518, 2012.
[5] 
Rassi, A., Jr; Rassi, A.; Marin-Neto, J.A. Chagas disease. Lancet,  2010, 375(9723), 1388-1402.
[http://dx.doi.org/10.1016/S0140-6736(10)60061-X] [PMID:  20399979] 
[6] 
World Health Organization. Chagas disease (also known as American trypanosomiasis), 2020. Available at: https://www.who.int/en/news-room/fact-sheets/detail/chagas-disease(american-trypanosomiasis) (Accessed: 26 November, 2020).
[7] 
Bernardes, L.S.C.; Zani, C.L.; Carvalho, I. Trypanosomatidae diseases: from the current therapy to the efficacious role of trypanothione reductase in drug discovery. Curr. Med. Chem.,  2013, 20(21), 2673-2696.
[http://dx.doi.org/10.2174/0929867311320210005] [PMID:  23410156] 
[8] 
Bandyopadhyay, D.; Samano, S.; Villalobos-Rocha, J.C.; Sanchez-Torres, L.E.; Nogueda-Torres, B.; Rivera, G.; Banik, B.K. A practical green synthesis, and biological
evaluation of benzimidazoles against tropical diseases: Chagas and Leishmaniasis.  Curr. Med. Chem.,  2017, 24(41), 4714-4725.
[http://dx.doi.org/10.2174/0929867325666171201101807] [PMID: 23317160] 
[9] 
World Health Organization. Dengue and Severe Dengue, 2016. Available at: https://www.who.int/en/news-room/fact-sheets/detail/dengue-and-severe-dengue (Accessed: 26 November, 2020).
[10] 
Chen, C.S.; Lin, Y.L.; Jadhav, A. Antiviral agents. WO Patent (A1) 2,018,026,812 2018.
[11] 
Asekunowo, P.O.; Haque, R.A.; Razali, M.R.; Avicor, S.W.; Wajidi, M.F.F. Synthesis and characterization of nitrile functionalized silver(I)-N-heterocyclic carbene complexes: DNA binding, cleavage studies, antibacterial properties and mosquitocidal activity against the dengue vector, Aedes albopictus. Eur. J. Med. Chem.,  2018, 150, 601-615.
[http://dx.doi.org/10.1016/j.ejmech.2018.03.029] [PMID:  29550733] 
[12] 
World Health Organization. Dracunliasis 2018. Available at: https://www.who.int/dracunculiasis/en/ (Accessed: 26 November, 2020).
[13] 
World Health Organization. Dracunculiasis (guinea-worm disease) 2020. Available at: https://www.who.int/en/news-room/fact-sheets/detail/dracunculiasis-(guinea-worm-disease) (Accessed: 26 November, 2020).
[14] 
Linington, R.; Navarro, G.; Pudhom, K.; Mckerrow, J. Novel semi-synthetic small molecules for the treatment parasitic disease. WO Patent (A2) 2,013,019,686 2013.
[15] 
World Health Organization. Echinococcosis 2020. Available at: https://www.who.int/echinococcosis/disease/en/ (Accessed: 26 November, 2020).
[16] 
D’Alessandro, A.; Rausch, R.L. New aspects of neotropical polycystic (Echinococcus vogeli) and unicystic (Echinococcus oligarthrus) echinococcosis. Clin. Microbiol. Rev.,  2008, 21(2), 380-401.
[http://dx.doi.org/10.1128/CMR.00050-07] [PMID:  18400802] 
[17] 
World Health Organization. Echinococcosis 2020. Available at: https://www.who.int/en/news-room/fact-sheets/detail/echinococcosis (Accessed: 26 November, 2020).
[18] 
do Espirito Santo, R.D.; Machado, M.G.M.; dos Santos, J.L.; Gonzalez, E.R.P.; Chin, C.M. Use of guanidine compounds in the treatment of neglected tropical diseases. Curr. Org. Chem.,  2014, 18, 2572-2602.
[http://dx.doi.org/10.2174/138527281820141028104429] 
[19] 
Zhang, H.; Liu, C.; Xue, J.; Duan, L.; Tao, Y.; Yao, J.; Wang, W.; Wei, Y.; Xu, L.; Zheng, Q.; Huo, L.; Tu, Z.; Zhao, Y.; Chen, Y.; Liu, N. Chinese medicinal composition
for treating tumor, ulcer and trauma hemorrhage on skin,
eczema, scabies, bromhidrosis, tinea pedis and onychomycosis and preparation method thereof. CN106,727,581A, 2017.
[20] 
World Health Organization. Foodborne Trematodiases.,  Available at: https://www.who.int/en/news-room/fact-sheets/detail/foodborne-trematodiases (Accessed: 26 November, 2020).
[21] 
Keiser, J.; Utzinger, J. Food-borne trematodiasis: current chemotherapy and advances with artemisinins and synthetic trioxolanes. Trends Parasitol.,  2007, 23(11), 555-562.
[http://dx.doi.org/10.1016/j.pt.2007.07.012] [PMID:  17950667] 
[22] 
Cayla, M.; Rojas, F.; Silvester, E.; Venter, F.; Matthews, K.R. African trypanosomes. Parasit. Vectors,  2019, 12(1), 190.
[http://dx.doi.org/10.1186/s13071-019-3355-5] [PMID:  31036044] 
[23] 
World Health Organization. Human African trypanosomiasis.,  Available at: https://www.who.int/trypanosomiasis_ african/disease/en/ (Accessed: 26 November, 2020).
[24] 
Sutherland, C.S.; Tediosi, F. Is the elimination of ‘sleeping sickness’ affordable? Who will pay the price? Assessing the financial burden for the elimination of human African trypanosomiasis Trypanosoma brucei gambiense in sub-Saharan Africa. BMJ Glob. Health,  2019, 4(2)e001173
[http://dx.doi.org/10.1136/bmjgh-2018-001173] [PMID:  31139437] 
[25] 
World Health Organization. Human African trypanosomiasis.,  Available at: https://www.who.int/trypanosomiasis_ african/news/progress-on-eliminating-hat-as-public-health-problem/en/ (Accessed: 26 November, 2020).
[26] 
World Health Organization. Trypanosomiasis. Human
African (Sleeping Sickness)  Available at: https://www. who.int/en/news-room/fact-sheets/detail/trypanosomiasis-human-african-(sleeping-sickness) (Accessed: 26 November, 2020).
[27] 
Hiltensperger, G.; Jones, N.G.; Niedermeier, S.; Stich, A.; Kaiser, M.; Jung, J.; Puhl, S.; Damme, A.; Braunschweig, H.; Meinel, L.; Engstler, M.; Holzgrabe, U. Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei. J. Med. Chem.,  2012, 55(6), 2538-2548.
[http://dx.doi.org/10.1021/jm101439s] [PMID:  22376072] 
[28] 
Winter, I.; Lockhauserbäumer, J.; Lallinger-Kube, G.; Schobert, R.; Ersfeld, K.; Biersack, B. Anti-trypanosomal activity of cationic N-heterocyclic carbene gold(I) complexes. Mol. Biochem. Parasitol.,  2017, 214, 112-120.
[http://dx.doi.org/10.1016/j.molbiopara.2017.05.001] [PMID:  28522152] 
[29] 
World Health Organization. Leishmaniasis. Vector control  Available at: https://www.who.int/leishmaniasis/vector-control/en/ (Accessed: 26 November, 2020).
[30] 
World Health Organization. Leishmaniasis  Available at: https://www.who.int/en/news-room/fact-sheets/detail/leishmaniasis  (Accessed: 26 November, 2020).
[31] 
World Health Organization. Report of a meeting of the WHO expert committee on the control of leishmaniases. WHO technical report series,  2010, 949, 54-73.
[32] 
Dos Santos Fernandes, G.F.; Pavan, A.R.; Dos Santos, J.L. Heterocyclic N-oxides - a promising class of agents against tuberculosis, malaria and neglected tropical diseases. Curr. Pharm. Des.,  2018, 24(12), 1325-1340.
[http://dx.doi.org/10.2174/1381612824666180417122625] [PMID:  29663875] 
[33] 
National Institute of Allergy and Infectious Diseases. Leprosy (Hansen’s disease) 2015. Available at: https://www. niaid.nih.gov/diseases-conditions/leprosy-hansens-disease (Accessed: 26 November, 2020).
[34] 
World Health Organization. Leprosy  Available at: https://www.who.int/en/news-room/fact-sheets/detail-/leprosy (Accessed: 26 November, 2020).
[35] 
Willand, N.; Deprez, B.; Baulard, A.; Brodin, P.; Flipo, M.; Maingot, L. Composes bicycliques ayant une activite potentialisatrice de l'activite d'un antibiotique actif contre les
mycobacteries-composition et produit pharmaceutiques
comprenant de tels composes F.R. Patent (A1) 3,000,065, 2014.
[36] 
Centers of Disease Control and Prevention (USA). What is Hansen’s disease?,  Available at: https://www.cdc.gov/lep-rosy/about/about.html (Accessed: 26 November, 2020).
[37] 
World Health Organization. Lymphatic Filariasis.,  Available at: https://www.who.int/en/news-room/fact-sheets/de-tail/lymphatic-filariasis (Accessed: 26 November, 2020).
[38] 
Centers of Disease Control and Prevention (USA). Parasites-Lymphatic Filariasis.,  Available at: https://www.cdc. gov/parasites/lymphaticfilariasis/treatment.html (Accessed: 26 November, 2020).
[39] 
Mandvikar, A.; Hande, S.V.; Yeole, P.; Goswami, K.; Reddy, M.V.R. Therapeutic potential of novel heterocyclic thiazolidine compounds against human lymphatic filarial parasite: an in vitro study. Int. J. Pharm. Sci. Res.,  2016, 7(4), 1480-1492.
[http://dx.doi.org/10.13040/IJPSR.0975-8232.] 
[40] 
World Health Organization. Neglected tropical diseases.,  Available at: https://www.who.int/neglected_diseases/-diseases/mycetoma-chromoblastomycosis-deep-mycoses/- en/index1.html (Accessed: 26 November, 2020).
[41] 
World Health Organization. Mycetoma  Available at: https://www.who.int/en/news-room/fact-sheets/detail/mycetoma (Accessed: 26 November, 2020).
[42] 
Lu, H. Novel antifungal infection drugs as well as preparation method and applications thereof. CN Patent (A)
107,556,294 2018.
[43] 
World Health Organization. Onchocerciasis  Available at: https://www.who.int/en/news-room/fact-sheets/detail/onchocerciasis  (Accessed: 26 November, 2020).
[44] 
Centers of Disease Control and Prevention (USA). Parasites - Onchocerciasis (also known as River Blindness)  Available at: https://www.cdc.gov/parasites/onchocercia-sis/treatment.html (Accessed: 26 November, 2020).
[45] 
Centers of Disease Control and Prevention (USA). Onchocerciasis FAQs (also known as River Blindness)  Available at: https://www.cdc.gov/parasites/onchocerciasis/gen_ info/faqs.html (Accessed: 26 November, 2020).
[46] 
Chen, S.; Jiang, J.; Zhang, J.; Xie, Y. Benzoimidazolylpyrazine compounds for inflammation and immune-related
uses. U.S. Patent 6,043,045 2006.
[47] 
Oloyede, G.K.; Onocha, P.A.; Oke, J.M. Mannich synthesis of 2-(thiazol-4-yl)-1H-benzimidazole-2-methylene piperazinyl (2,5-diamino-1,3,4-thiadiazolyl) oxamide and evaluation of the filaricidal activity. Am. Eur J. Sci. Res.,  2011, 6(2), 116-122.
[48] 
World Health Organization. Epidemiology and burden of disease.,  Available at: https://www.who.int/rabies/epide-miology/en/ (Accessed: 26 November, 2020).
[49] 
World Health Organization. Rabies  Available at: https://www.who.int/en/news-room/fact-sheets/detail/rabies (Accessed: 26 November, 2020).
[50] 
Krogstad, P.; Jung, M.E.; Zuo, J.; Xing, Y. Potent antiviral
pyrazolopyridine compounds. WO Patent (A1)
2,017,053,604 2017.
[51] 
Sasikumar, P.G.N.; Prasad, A.; Naremaddepalli, S.S.S.; Ramachandra, M. Cyclic substituted-1,3,4-oxadiazole and
thiadiazole compounds as immunomodulators. WO Patent
(A1) 2,018,051,255 2018.
[52] 
World Health Organization. Rabies: Epidemiology and
burden of disease 2017. Available at: https://www.who. int/neglecteddiseases/diseases/scabies/en/ (Accessed: 26 November, 2020).
[53] 
International Alliance for the Control of Scabies (IACS).  Available at: http://www.controlscabies.org/ (Accessed: 26 November, 2020).
[54] 
World Health Organization. Schistosomiasis  Available at: https://www.who.int/en/news-room/fact-sheets/detail/schistosomiasis  (Accessed: 26 November, 2020).
[55] 
World Health Organization. Schistosomiasis. What is schistosomiasis?  Available at: https://www.who.int/schisto-somiasis/disease/en/ (Accessed: 26 November, 2020).
[56] 
de Brito, M.R.M.; Peláez, W.J.; Faillace, M.S.; Militão, G.C.G.; Almeida, J.R.G.S.; Argüello, G.A.; Szakonyi, Z.; Fülöp, F.; Salvadori, M.C.; Teixeira, F.S.; Freitas, R.M.; Pinto, P.L.S.; Mengarda, A.C.; Silva, M.P.N.; Da Silva Filho, A.A.; de Moraes, J. Cyclohexene-fused 1,3-oxazines with selective antibacterial and antiparasitic action and low cytotoxic effects. Toxicol. In Vitro,  2017, 44, 273-279.
[http://dx.doi.org/10.1016/j.tiv.2017.07.021] [PMID:  28755871] 
[57] 
World Health Organization. Neglected tropical diseases. Preventive chemotherapy for helminth diseases: progress
report 2014. Available at: https://www.who.int/neglected_ diseases/resources/who_wer9108/en/ (Accessed: 26 November, 2020).
[58] 
World Health Organization. Soil Transmitted Helminth Infections.,  Available at: https://www.who.int/en/news-room/fact-sheets/detail/soil-transmitted-helminth-infections (Accessed: 26 November, 2020).
[59] 
Balaji, P.N.; Ranganayakulu, D.; Reddy, G.V.S. Synthesis, in vitro evaluation for anthelmintic and antimicrobial activity for the novel thiazolidine-4-one incorporate substituted chloro-quinoline. Asian J. Pharm. Pharmacol.,  2017, 3(1), 9-15.
[60] 
Husain, A.; Varshney, M.M.; Parcha, V.; Ahmad, A.; Khan, S.A. Nalidixic acid Schiff bases: synthesis and biological evaluation. Lett. Drug Des. Discov.,  2018, 15, 103-111.
[http://dx.doi.org/10.2174/1570180814666170710160751] 
[61] 
World Health Organization. Snakebite Envenoming.,  Available at: https://www.who.int/en/news-room/fact-sheets/detail/snakebite-envenoming (Accessed: 26 November, 2020).
[62] 
Slade, H.B. Method for the treatment of dermal lesions
caused by envenomation. WO Patent (A2) 0,174,343 2010.
[63] 
Centers of Disease Control and Prevention (USA). Parasites - Taeniasis  Available at: https://www.cdc.gov/-parasites/taeniasis/index.html (Accessed: 26 November, 2020).
[64] 
World Health Organization. Taeniasis  Available at: https://www.who.int/taeniasis/disease/en/ (Accessed: 26 November, 2020).
[65] 
World Health Organization. Taeniasis/Cysticercosis.  Available at: https://www.who.int/en/news-room/fact-sheets/detail/taeniasis-cysticercosis (Accessed: 26 November, 2020).
[66] 
Centers of Disease Control and Prevention (USA). Parasites-Taeniasis: Treatment  Available at: https://www.cdc. gov/parasites/taeniasis/treatment.html (Accessed: 26 November, 2020).
[67] 
Centers of Disease Control and Prevention (USA). Hygiene-related Diseases.,  Available at: https://www.cdc.gov/healthywater/hygiene/disease/trachoma.html (Accessed: 26 November, 2020).
[68] 
World Health Organization. Trachoma 2017. Available at: https://www.who.int/en/news-room/fact-sheets/detail/trachoma (Accessed: 26 November, 2020).
[69] 
Finn, P.W.; Charlton, M.; Edmund, G.; Jirgensons, A.; Loza, E.  2-amino-N-(arylsulfinyl)-acetamide compounds as
inhibitors of bacterial aminoacyl-tRNA synthetase. WO
Patent (A1) 2,018,065,611 2019.
[70] 
Werner, M.H.; Kelly, T.A. Compositions and methods for
inhibiting kinases. WO Patent (A1) 2,016,172,528 2016.
[71] 
Emerson, P.M.; Ngondi, J. Mass antibiotic treatment alone does not eliminate ocular chlamydial infection. PLoS Negl. Trop. Dis.,  2009, 3(3)e394
[http://dx.doi.org/10.1371/journal.pntd.0000394] [PMID:  19333370] 
[72] 
World Health Organization. Neglected tropical diseases. Accelerating yaws eradication: antibiotic added to WHO’s
essential medicines list. ,  Available at: https://www. who.int/neglected_diseases/news/accelerating_yaws_eradication/en/ (Accessed: 26 November, 2020).
[73] 
World Health Organization. Yaws 2012. Available at: http://www.who.int/en/news-room/fact-sheets/detail/yaws (Accessed: 26 November, 2020).
[74] 
Bahadoor, A.; Castro, A.C.; Chan, L.K.; Keaney, G.F.; Nevalainen, M.; Nevalainen, V.; Peluso, S.; Snyder, D.A.; Tibbitts, T.T.  Tetrazolones as inhibitors of fatty acid synthase. WO Patent (A1) 2,011,140,190 2011.
[75] 
Bahadoor, A.; Castro, A.C.; Chan, L.K.; Keaney, G.F.; Nevalainen, M.; Nevalainen, V.; Peluso, S.; Tibbitts, T.T. Triazoles as inhibitors of fatty acid synthase. WO Patent (A1) 2,011,140,296 2011.

Rights & Permissions Print Cite

Article Metrics

22

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/0929867327666200219141652	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X

Current Medicinal Chemistry

Heterocycles in the Treatment of Neglected Tropical Diseases

Abstract Play Pause

Related Journals

Related Books

Related Articles

Abstract