Inhibition of Chikungunya Virus Replication by 1-[(2-Methylbenzimidazol-1-yl) Methyl]-2-Oxo-Indolin-3-ylidene] Amino] Thiourea(MBZM-N-IBT)

Abstract

Chikungunya virus (CHIKV) infection is one of the most challenging human Arboviral infections with global significance and without any specific antiviral. In this investigation, 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (MBZM-N-IBT) was synthesised as a molecular hybrid of 2-methyl benzimidazole and isatin-β-thiosemicarbazone and its anti-CHIKV property was evaluated. The release of infectious virus particles was calculated by plaque assay, expression profile of viral RNA was estimated by RT-PCR and viral protein profiles were assessed by Western blot and FACS analyses. The safety index of MBZM-N-IBT was found to be >21. The CHIKV infectious viral particle formation was abrogated around 76.02% by MBZM-N-IBT during infection in mammalian system and the viral RNA synthesis was reduced by 65.53% and 23.71% for nsP2 and E1 respectively. Surprisingly, the viral protein levels were reduced by 97% for both nsP2 and E2. In the time-of-addition experiment it abrogated viral infection at early as well as late phase of viral life cycle, which indicates about multiple mechanisms for its anti-CHIKV action. In silico analysis justified development of MBZM-N-IBT with good affinities for potential target proteins of CHIKV and related virus. With predictions of good drug-likeness property, it shows potential of a drug candidate which needs further experimental validation.

Chikungunya, a Global Threat Currently Circulating in Latin America

“…For instance, chloroquine has been suggested as a drug with prophylactic and therapeutic effects apparently by impairing endosomal-mediated virus entry during early stages of virus replication [90]. Other anti-parasite agents, such as ivermectin and a benzimidazole-derived drug, have showed effects on replication at early and late stages of infection [91,92]. Doxycycline combined with ribavirin effectively inhibited CHIKV replication and attenuated its infectivity in vivo in animal models [93].…”

Antiviral activity of N-ω-Chloroacetyl-L-Ornithine on in vitro replication of Chikungunya virus

“…Several compounds have been proposed, including chloroquine (Brighton, 1984), ribavirin (Leyssen et al, 2008), arbidol (Delogu et al, 2017), harringtonine (Kaur et al, 2013), suramina (Albulescu et al, 2015) and silymarin (Lani et al, 2015) that act in different stages of the viral replication cycle, however, have certain disadvantages that make them ineffective for use in CHIKV infections. (Mishra et al, 2016). Mouce et al, 2016a, 2016b showed that PAs, putrescine, spermidine and spermine are important in the replication of a large variety of RNA viruses, including Chikungunya, as well as their participation in other molecular processes such as the packaging of the viral genome; in DNA viruses the polyamines stabilize the negatively charged genome within the virion particle, among them, the bacteriophage T7 virions cytomegalovirus (CMV) (Kalejta, 2008), and vaccinia virus are found (Lanzer, Holowezak., 1975).…”

Vaccine and Therapeutic Options To Control Chikungunya Virus

“…For example, 22 distinct benzouracil-coumarin-arene compounds were synthesized, but only 5 were active against CHIKV in Vero cell culture (107). In contrast, distinct elements that had not been shown to have antiviral activity but were projected to be effective in combination by in silico analysis were effective in the case of a thiosemicarbazone with a benzimidazole group attached (109). Unfortunately, while these combination compounds, particularly peptides, are designed to show high specificity and selectivity, they frequently require extensive large-scale production steps, which may limit their manufacturability.…”