Synthesis and antimicrobial studies of novel 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones

Figures & data

Table 1.  Analytical data for compounds 1–16.

Entry	R	R^1	R^2	Yield (%)	Melting point (°C)	Mass (M+1)^+
1	H	H	H	49	185–186	292.22
2	H	H	F	47	198–199	328.17
3	H	F	H	43	192–193	327.42 (M^+)
4	H	H	Cl	48	174–175	359.13 (M^+); 361 (M+2)
5	Cl	H	H	52	218	—
6	H	H	CH3	59	160–162	320.21
7	H	H	OCH3	49	174–175	351.38 (M^+)
8	H	OCH3	H	53	160–161	—
9	H	H	H	78	168–170	441.1119
10	H	H	F	81	202–203	477.2324
11	H	F	H	79	180–182	—
12	H	H	Cl	76	224–226	509.1408; 510.1392 (M+2)
13	Cl	H	H	72	198–200	—
14	H	H	CH3	89	169–170	469.1983
15	H	H	OCH3	81	148–150	501.2298
16	H	OCH3	H	79	159–161	500.9981

The observed m/z value is within ±0.4% from their theoretical value.

Scheme 1.  Reagent and conditions: (a) EtOH/warm, room temperature, 2–10 days and (b) MeOH-CHCl₃, H₂NNHCSNHPh/H⁺, reflux, 90–100°C 4 h.

Table 2.  Correlations in the H,H-COSY and NOESY spectra of compound 9.

Signal (d (ppm))	Correlations in H,H-COSY	Correlations in NOESY
7.59 (d, 2H, H-4b)	7.46	7.46 (s), 7.21 (s)
7.46 (dd, 2H, H-4c)	7.59, 7.21	7.59 (s), 7.21 (s)
7.35–7.39 (m, 4H, H-2″/H-4″)	7.29–7.32	7.29–7.32 (s), 4.41 (s), 4.29 (s)
7.25–7.30 (m, 6H, H-2′″/H-4′″, H-2″″/H-4″″)	7.35–7.39	7.35–7.39
7.21 (t, 1H, H-4d)	7.46	7.59, 7.46
4.41 (d, 1H, H-2a)	2.48	7.35–7.39 (s), 4.29, 2.48 (s), 1.79 (w)
4.29 (s, 1H, H-4a)	3.11, 1.46 (w)	7.35–7.39 (s), 4.41, 3.11 (s), 1.79 (w)
3.11 (s, 1H, H-5)	4.29 (s), 2.48 (w) 1.79 (w), 1.46	7.35–7.39 (s), 4.29 (s), 1.79, 1.46
2.83 (m, 1H, H-7a)	1.46, 1.79, 1.46	7.35–7.39 (w), 1.46
2.48 (b s, 1H, H-1)	4.41 (s), 1.79, 1.46, 3.11 (w)	7.35–7.39 (w), 4.41 (s), 1.46 (w)
1.79 (dd, 3H, H-6e, H-8e and NH)	3.11, 2.83, 1.46	7.35–7.39, 1.46
1.46 (m, 3H, H-6a, H-8a and H-7e)	4.29 (w), 3.11, 2.83, 1.46	1.79, 2.83
9.21 (s, 1H, NHCS)	—	8.43, 3.11
8.43 (s, 1H, CSNHPh)	—	9.21

s, strong correlation; w, weak correlation.

Table 3.  Correlations in the HSQC spectrum of compound 9.

Signal (d (ppm))	Correlations in HSQC
7.59 (d, 2H, H-4b)	128.42
7.46 (dd, 2H, H-4c)	128.39
7.35–7.39 (m, 4H, H-2″/H-4″)	127.61–126.89
7.33 (m, 6H, H-2′″/H-4′″, H-2″″/H-4″″)	127.61–126.89
7.21 (t, 1H, H-4d)	123.67
4.41 (d, 1H, H-2a)	65.01
4.29 (s, 1H, H-4a)	63.98
3.11 (s, 1H, H-5e)	36.34
2.83 (m, 1H, H-7a)	20.51
2.48 (b s, 1H, H-1e)	45.01
1.79 (dd, 3H, H-6e, H-8e and NH)	25.98, 29.08
1.46 (m, 3H, H-6a, H-8a and H-7e)	25.98, 29.08, 20.51
9.21 (s, 1H, NHCS)	—
8.43 (s, 1H, CSNHPh)	—

Figure 1.  Correlations between the protons that are in “W” arrangements, from the H,H-COSY spectrum of compound 9.

Figure 2.  Non-bonded interaction between C–H(5) and N–NH group.

Figure 3.  Twin-chair conformation with equatorial orientation of the phenyl groups at C-2 and C-4; supported by the NOE observed in the NOESY spectrum of compound 9. For clarity, the NOE between the ortho and ring protons is shown by red colour lines.

Table 4.  Antibacterial activity of compounds 9–16 against selected bacterial strains (MIC in μg/mL).

Compound	Minimum inhibitory concentration (MIC) in µg/mL
	S. aureus	B. subtils	S. tyhpi	E. coli	K. pneumonia
9	200	100	200	100	200
10	50	6.25	12.5	50	—
11	25	6.25	100	25	100
12	100	50	50	100	12.5
13	25	25	6.25	25	100
14	100	50	50	12.5	50
15	100	100	50	100	12.5
16	50	100	200	200	—
Ciprofloxacin	25	12.5	50	25	25

—, no inhibition even at maximum concentration 200 µg/mL.

Table 5.  Antifungal activity of compounds 9–16 against selected fungal strains (MIC in μg/mL).

Compound	Minimum inhibitory concentration (MIC) in µg/mL
	C. albicans	R. oryzae	C. neoformans	A. niger	A. flavus
9	200	200	100	200	—
10	50	50	50	12.5	50
11	6.25	25	12.5	50	100
12	100	50	6.25	100	50
13	6.25	25	6.25	100	50
14	100	100	50	25	—
15	25	25	100	50	25
16	6.25	50	100	100	25
Amphotericin -B	25	25	25	50	50

—, no inhibition even at maximum concentration 200 µg/mL.

Figure 4.  Comparison of potency of compounds 9–16 with ciprofloxacin (as standard) against bacterial strains from serial dilution method. Scheme 1: Schematic diagram showing the synthesis of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones.

Figure 5.  Comparison of potency of compounds 9–16 with amphotericin B (as standard) against fungal strains from serial dilution method.