5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus

Abstract

Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.

Antiviral Activity of Benzotriazole Based Derivatives

“…Moreover, the substitution of the aliphatic side chain with an aromatic moiety on the amide nitrogen (compounds 8a,b,c-15a,b,c) dramatically cancels the antiviral activity (not listed in a table); on the contrary, the corresponding chlorinederivatives have shown extensive antiviral activity against CV-B5, BVDV, hRSV [16] and orthohantavirus (HTNV) [25] with EC 50 values ranged between 3 and 27 µM.…”

“…The potency increases as the chain length up to a maximum of 4 linear carbon atoms (compound 18c showed an EC 50 value of 5.5 µM). Among urea derivatives already published for their antiviral activity against orthohantavirus (16d-18d, 20d-26d) [25], hRSV (16d-18d, 20d-26d) [16] and b) [17], compounds 16d-18d, 20d-26d had turned out completely inactive when tested against CV-B5 and Sb-1, while compounds 16a,b-26a,b were active against CV-B5 and Sb-1 but inactive when tested against hRSV. In this series, as previously seen with benzamide derivative, the insertion of an aromatic moiety on the urea nitrogen leads to total loss of activity.…”

“…b Compound concentration (µM) required to reduce the plaque number of the indicated virus by 50% in Vero76 monolayers. of urea derivatives 16a,b,c-19a,b,c, 16d-18d 16a >100 10 >100 [17] 16b >100 >100 >100 [17] 16c >100 53 >100 -16d >100 >100 >100 [16,25] Compounds Vero76 CV-B5 Sb-1 Ref -aCC50 bEC50 --17a 100 >100 >100 [17] 17b >100 >100 >100 [17] 17c >100 6.9 20.5 -17d 30 >30 >30 [16,25] 18a >100 >100 >100 [17] 18b >100 >100 >100 [17] 18c >100 5.5 17.5 -18d 90 >95 >95 [16,25] 19a >100 16 >100 [17] 19b >100 53 >100 [17] 19c >100 >100 >100 - The antiviral activity profile of these newly designed and synthesised compounds was compared with others that we previously reported, to extend the SARs analysis. In the series of N-(4- (R-2H-benzo[d] [1][2][3]triazol-2-yl)phenyl)alkylamides, the introduction of a fluorine atom in position 4, resulted in a power increase on both viral strains if compared to the parental compounds without any substituent on the benzotriazole scaffold or with methyl groups which were found only slightly active, while derivatives with two chlorine atoms were totally inactive ( Table 3).…”

Novel therapeutic approaches toward Hantaan virus and its clinical features’ similarity with COVID-19

“…Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d] 1 2, 3 triazoles could be promising candidates for further investigation as a potential treatment of Hantaan viral diseases. [ 40 ]…”

Antiviral Agents: Discovery to Resistance

“…Antiviral agents are not available against many emerging and neglected viruses. This issue features four research papers reporting new antiviral compound candidates against zika virus [7,8], hantaan virus [9] and herpes B virus [10]. Measles virus is considered a re-emerging virus due to recent decline in vaccine coverage.…”