Synthesis of 5-(4-hydroxy-3-methylphenyl)-5-(substituted phenyl)-4, 5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives with anti-viral activity

Figures & data

Table I.  Physical constants of the synthesized compounds..

Compound	R	Yield (%)	M.P (°C)	Mol. Formula	Mol. Wt
4a	4-Methoxy phenyl-	72	119	C23H21N3O3	387.4
4b	4-Chloro phenyl-	78	166	C22H18ClN3O2	391.8
4c	4-Dimethylamino phenyl-	66	110	C24H24N4O2	400.47
4d	Phenyl-	80	140	C22H19N3O2	357.4
4e	3,4-Dimethoxy phenyl-	82	138	C24H23N3O4	417.4
4f	3,4,5-Trimethoxy phenyl-	86	186	C25H25N3O5	447.4
4 g	Furfuryl-	94	152	C20H17N3O3	347.3
4 h	4-Fluoro phenyl-	86	146	C22H18FN3O2	375.3
4i	2-Chloro phenyl-	80	194	C22H18ClN3O2	391.8
4j	2,6-Dichloro phenyl-	78	212	C22H17Cl2N3O2	426.2
4k	3-Nitro phenyl-	65	112	C22H18N4O4	402.4

Recrystalization: Methanol

Table II.  Cytotoxicity and antiviral activity of synthesized compounds in HeL cell cultures..

		Minimum inhibitory concentration ^b (μg/mL)
Compound	Minimum cytotoxic concentration ^a (μg/mL)	Herpes simplex virus-1 (KOS)	Herpes simplex virus-2 (G)	Vaccinia virus	Vesicular stomatitis virus	Herpes simplex virus-1 TK-KOS ACV^r
4a	40	>8	>8	8	>8	>8
4b	200	>8	40	8	>8	>8
4c	200	>40	>40	>40	>40	>40
4d	40	>8	>8	>8	>8	>8
4e	≥ 1.6	8	>40	>40	>40	>40
4f	≥ 1.6	>200	>200	>200	>200	>200
4 g	40	≥ 1.6	≥ 1.6	>1.6	>1.6	>1.6
4 h	200	40	>8	8	26	8
4i	200	8	8	8	>8	8
4j	200	>8	24	40	40	>8
4k	40	8	8	8	>8	8
Brivudin	>200	0.064	40	4	>200	>200
Ribavirin	>200	89	>200	120	120	>200
Acyclovir	>200	0.72	0.32	24	>200	89
Ganciclovir	>100	0.08	0.016	100	>100	22

^a Required to cause a microscopically detectable alteration of normal cell morphology

^b Required to reduce virus-induced cytopathogenicity by 50%.

Table III.  Cytotoxicity and antiviral activity of synthesized compounds in HeLa cell cultures..

		Minimum inhibitory concentration ^b (μg/mL)
Compound	Minimum cytotoxic concentration^a (μg/mL)	Vesicular stomatitis virus	Coxsackie virus B4	Respiratory syncytial virus
4a	100	>8	>8	>8
4b	8	>40	8	>40
4c	200	>8	>8	>8
4d	8	>40	>40	>40
4e	200	>40	>40	>40
4f	8	>200	>40	>200
4 g	>200	200	>200	>200
4 h	40	>8	>8	>8
4i	8	>1.6	>40	>40
4j	40	>8	>40	>8
4k	100	>8	>8	>8
Brivudin	>200	>200	>200	>200
(S)-DHPA	>200	120	>200	>200
Ribavirin	>200	8	120	8

^a Required to cause a microscopically detectable alteration of normal cell morphology

^b Required to reduce virus-induced cytopathogenicity by 50%.

Table IV.  Cytotoxicity and antiviral activity of synthesized compounds in Vero cell cultures..

		Minimum inhibitory concentration ^b (μg/mL)
Compound	Minimum cytotoxic concentration^a (μg/mL)	Para-influenza-3 virus	Reovirus-1	Sindbis virus	Coxsackie virus B4	Punta Toro virus
4a	40	>8	>8	>8	>8	>8
4b	40	>8	>8	8	>8	>8
4c	200	>40	>40	40	>40	>40
4d	40	>8	>8	>8	>8	>8
4e	≥ 1.6	>40	>40	>40	>40	>40
4f	≥ 1.6	>200	>200	>200	>200	>200
4 g	40	≥ 1.6	≥ 1.6	>1.6	>1.6	>1.6
4 h	200	>40	40	24	>8	>8
4i	40	8	8	8	>8	8
4j	40	>8	>8	>8	>8	>8
4k	40	8	8	8	>8	8
Brivudin	>200	>200	>200	>200	>200	>200
(S)-DHPA	>200	120	>200	>200	120	>200
Ribavirin	>200	8	120	8	>200	89

^a Required to cause a microscopically detectable alteration of normal cell morphology

^b Required to reduce virus-induced cytopathogenicity by 50%.

Scheme 1 Synthesis of 5-(4-hydroxy-3-methylphenyl)-5-(substituted phenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives.