Synthesis of Novel Valine-based Dipeptide Carboxamide Bearing Benzene Sulfonamide Moiety as Antimalarial Agent


  • James. A. Ezugwu University of Nigeria, Nsukka, 410001, Enugu State, Nigeria
  • Uchechukwu C. Okoro University of Nigeria, Nsukka, 410001, Enugu State, Nigeria
  • Mercy A. Ezeokonkwo University of Nigeria, Nsukka, 410001, Enugu State, Nigeria
  • China Raju Bhimapaka Division, CSIR-India Institute of Chemical Technology, Hyderabad, Telangana, India


Valine-dipeptide, carboxamide, benzensulphonamoyl butanamide, antimalarial.


Communication in Physical Sciences 2020, 5(2): 176-197

Authors: James A. Ezugwu, *Ucheckukwu. C. Okoro, Mercy A. Ezeokonkwo, and China R. Bhimapaka

Received 15 April 2020/Accepted 14 May 2020


Syntheses of eleven novel Valine-based dipeptide carboxamide derivatives bearing benzensulphonamide are reported. These were achieved by facile amidation reaction of p- substituted benzenesulphonamoyl alkanamides with 2-amino-4-methyl-N-substituted phenyl butanamide using classical peptide coupling reagents. The chemical structures of the synthesized compounds were established by 1H-NMR, 13C-NMR, ESI- HRMS, and FT-IR spectroscopic techniques. The synthesized compounds were evaluated for in vivo antimalarial against P. berghei. Haematological analysis was also evaluated on the synthesized compounds. At 50mg/kg body weight, the compounds 8e, 8g, 8i, 8k, 8d and 8h inhibited the multiplication of the parasite by 46-71% on day seven of post-treatment exposure comparable to the 67% reduction with artemisinin.


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Author Biographies

James. A. Ezugwu, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

Department of Pure and Industrial Chemistry

Uchechukwu C. Okoro, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

Department of Pure and Industrial Chemistry

Mercy A. Ezeokonkwo, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria

Department of Pure and Industrial Chemistry

China Raju Bhimapaka, Division, CSIR-India Institute of Chemical Technology, Hyderabad, Telangana, India

Organic synthesis and process chemistry


Agrawal, V. K., Sinha, S., Bano, S. & Khadikar, P.

V. 2001), QSAR studies on antimalarial 2,4- diamino-6-quinazoline sulphonamides. Acta Microbiologica et Immunologica Hungarica, 48, 1, pp. 17-26.

Bag S, Tulsan R, Sood A, Cho H, Redjeb H, Zhou W, et al., (2015), Sulfonamides as multifunctional agents for Alzheimer’s disease. Bioorganic and Medicinal Chemistry Letters, 25, 626-30.

Bell, A. (2011), Antimalarial peptides: the long and the short of it. Current Pharmaceutical Design, 17, 25, pp. 2719–2731.

Brown. B. (1976), A. Textbook of Hematology principle procedures. 2nd edition. Lea and Fibiger. Philadelphia. USA, pp.56-58.

Carvalho, L. H., Brand~ao M. G. L., Santos-Filho,

D. Lopes, J. L. & Krettli, A. U. (1991), Antimalarial activity of crude extracts from Brazilian plants studied in vivo in Plasmodium berghei-infected mice and in vitro against Plasmodium falciparum in culture. Brazillian Journal of Medical and Biological Research, 24, pp.1113.

Chen, Z., Xu, W., Liu, K., Yang, S., Fan, H., Bhadury, P. S, et al., (2010) Synthesis and antiviral activity of 5-(4-chlorophenyl)- 1,3,4- thiadiazole sulfonamides. Molecules; 15, pp. 9046-56.

Conde, R., Zamudio, F. Z., Rodriguez, M. H. & Possani, L.D. (2000) Scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom. FEBS Letters, 471, pp. 165-168.

De Souza, N. B., Andrade I. M., Carmeiro, P. F., Jardim, G. A., de Melo, I. M., da Silva Junior, E.

N. & Krettli, A. U.(2014), Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against Plasmodium falciparum in vitro and in mice malaria studies. Mem Inst Oswaldo Cruz, pp. 109:546.

Domínguez, J. N., León, C., Rodrigues, J., Gamboa de Domínguez, N., Gut J. & Rosenthal P. J. (2005), Synthesis and antimalarial activity of sulfonamide chalcone derivatives. Farmaco 60, pp.307-11.

El-Sayed, N. S, El-Bendary, E. R., El-Ashry, S. M. & El-Kerdawy, M. .M. (2011. Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a] pyrimidines. European Journal of Pharmaceutical Chemistry, 46, pp. 3714-20.

Chollet, J., Matile, H. , Charman, S. A,, Creek, D. J., Charman, W. N., Tomas, J. S., Scheurer, C., Padmanilayam, M., Scorneaux, B., Dong, Y.,Wittlin, S., Brun, R. , Vennerstrom, J. L. (2006). Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine. Bioorganic and Medicinal Chemistry, 16, pp. 5542-5.

Ghorab, M. M., Ragab, F. A. & Hamed M, M. (2009), Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety. European Journal of Medicinal Chemistry 44, pp.4211-7.

Gwadz, R.W., Kaslow, D., Lee, J. Y., Maloy, W.L., Zaslo, M.. & Miller, L. H. (1989), Effects of magainins and cecropins on the sporogonic development of malaria parasites in mosquitoes. Infectious Immunology 57, pp. 2628-2633.

Hay, S. I., Guerra, C. A., Tatem, A., Atkinson, P. M. & Snow, R. W. (2005), Tropical infectious diseases: Urbanization, malaria transmission and disease burden in Africa. Nature Reviews Microbiology,3, pp. 81-90.

Hewitt, S. G. (1984), Manual for veterinary investigation, hematology and laboratory techniques, 3rd edition bulleting of ministry of Agric. Fishery, Food and Hematology, pp. 77-79

Keche, A. P., Hatnapure, G. D., Tale, R. H., Rodge,A, H., Birajdar, S. S. & Kamble, V. M. (2012), A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: Synthesis, anti-inflammatory and antimicrobial evaluation. Bioorganic and Medicinal Chemistry, 22, pp. 445-8.

Okokon, J. E, & Nwafor, P. A. (2009), Antiplasmodial activity of ethanolic root extract and fractions of Croton zambesicus. Journal of Ethnopharmacology, 121, pp. 74-78.

Parai, K. M., Panda, G., Srivastava, K. & Kumar, P.S. (2008), Design, synthesis and antimalarial activity of benzene and isoquinoline sulphonamide derivatives. Bioorganic and Medicinal Chemistry Letter, 18, 2, pp. 776-781.

Qi, Z., Verma, R., Gehring C., Yamaguchi, Y., Zhao, Y., Ryan, C. A. & Berkowitz, G. A. (2010), Ca2þ signaling by plant Arabidopsis thaliana pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca2þ channels. Proceeding of the National Academy of Sciences USA;107, pp. 21193.

Schalam, O. W. (1975). Textbook of veterinary Hematology, 3rd shieh.

Sharma, R. & Soman, S. S. (2015), Design and synthesis of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. European Journal of Medicinal Chemistry, 90, 342-50.

Thompson, A., Lin, W., Chu, E., Katritch, V., Wu, H., Vardy, E., Huang, X., Trapella, C., Guerrini, R., Calo, G., Roth, B. L., Cherezov, V. & Stevens, R. C. (2012), Structure of the nociceptin orphanin FQ receptor in complex witha peptide mimetic. Nature, pp. 485:495.

Ugwu D. I., Okoro, U. C., Ukoha. P. O, Okafor, S. Ibezim,, A. & Kumar, M. N. (2017), Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide. European Journal of Medicinal Chemistry, 135, pp. 349-69.

Ugwuja, D. I.., Okoro., Soman, S. S., Soni, R.., Okafor, S. N.& Ugwu., D. I. (2019), New peptide derived antimalaria and antimicrobial agents bearing sulphonamide moiety, Journal of Enzyme Inhibition and Medicinal Chemistry,34, 1, pp. 1388-1399.

Vizioli, J., Bulet, P., Ho_mann, J. A., Kafatos, F.C., Muller, H. & Dimopoulus, G. (2011). Gambicin:A novel immune responsive antimicrobial peptide from the malaria vector Anopheles gambiae. Proceeding of National Academy of Science, 98, 12, pp. 12630-12635.

Wasser, S. P., Reishi & Zhi, L (2005), Institute of evoluation press, university of Haifa, Mt. Camel, Haifa, Isreal, pp.603-622.

WHO (World Health Organisation)(2005). World Malaria Report. Accessed online on 7th July, 2019 at:

Wilkinson, B. L., Bornaghi,, L. F., Houston, T. A., Innocenti, A., Vullo, D., Supuran, C. T., & Poulsen, S. A. (2007), Carbonic anhydrase inhibitors: Inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides. European Journal of Medicinal Chemistry, 50, pp. 1651-1657.