A Comparison of Pyrimidinone Analogue Immunomodulators for Treatment ofPhlebovirusInfections in Mice

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Abstract
The substituted pyrimidinone immunomodulators 5-bromo-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (ABPP), 5-iodo-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (AIPP), 5-bromo-2,3-dihydro-2-imino-6-methyl-4(1H)-pyrimidinone (ABMP), 5-chloro-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (ACPP), 5-bromo-2,3-dihydro-2-iminp-6-(3-fluorophenyl)-4(1H)-pyrimidinone (ABmFPP) and 5-chloro-2,3-dihydro-2-imino-6-(2,3-difluorophenyl)-4(1H)-pyrimidinone (AComF2PP) were evaluated against the hepatotropic and immunosuppressive infection of mice induced by Punta Toro virus, a Phlebovirus related to Rift Valley fever virus. Using intraperitoneal (i.p.) treatments once daily for 3 days beginning 1 day prior to virus exposure, the order of efficacy was ABPP > ABmFPP > AComF2PP > AIPP > ABMP > ACPP, with prevention of death as end-point. Using single i.p. treatment 1 day prior to virus exposure, antiviral activity was seen in the order ABPP > ABmFPP > ABMP > AIPP > ACPP > AComF2PP. Three active pyrimidonones, ABPP, ABMP and AIPP, were given by gavage (p.o.) using the above 3-day treatment schedule. In this experiment, expanded parameters were used, with prevention of death seen as well as decreased hepatic icterus, as evidenced by lowered liver scores and serum glutamic oxalacetic and pyruvic transaminases. In addition, recoverable virus titres were reduced in the livers and sera of the mice. Greatest activity was seen using ABPP, followed by ABMP and then by AIPP. ABPP in doses of 100–800 mg kg−1 was markedly effective when administered p.o. in single treatments given as late as 24 hr after virus inoculation; a single dose, 400 mg kg−1, prevented death when given as late as 48 hr after virus exposure. In comparison of three once-daily, every-other-day, or every 2-day p.o. treatments, ABPP was most effective using the every-other-day regimen.