Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids

Figures & data

Table 1.  Crystallographic data for compounds 5b and 5l.

Data	5b	5l
Formula	C18H18BrN3O3S2	C20H22ClN3O3S3
Mr	468.38	484.04
Habit	Colourless tablet	Colourless tablet
Crystal size (mm)	0.2 × 0.2 × 0.1	0.2 × 0.2 × 0.1
Crystal system	Orthorhombic	Monoclinic
Space group	P212121	P21
Cell constants
a (Å)	5.5822 (1)	14.8104 (5)
b (Å)	17.8004 (3)	5.1998 (2)
c (Å )	20.1547 (4)	15.9657 (6)
α (°)	90	90
β (°)	90	111.615 (4)
γ (°)	90	90
V (Å^3)	2002.68	1143.08
Z	4	2
Dx (Mg m^−3)	1.553	1.406
μ (mm^−1)	2.29	4.27
Radiation	Mo-Kα	Cu-Kα
Wavelength (Å)	0.71073	1.54184
F (000)	952	504
T (°C)	−173	−173
2θmax	60	152
Completeness (%)	99.7	99.9 (to 2θ 145°)
Reflux measured	102274	24447
Reflux independant	5848	4320
Rint	0.039	0.037
Parameters	250	277901
Restraints	162	1
wR (F^2, all refluxes)	0.040	0.064
R (F, >4σ (F))	0.020	0.024
Flack parameter	−0.006 (3)	0.007 (10)
S	0.97	1.04
maximum Δρ (e Å^−3)	0.50	0.22

Figure 1.  The molecule of compound 5b in the crystal. Ellipsoids represent 50% probability levels.

Figure 2.  The molecule of compound 5l in the crystal. Ellipsoids represent 50% probability levels.

Figure 3.  Least-squares fit of the N-tosyl regions of 5b (numbered) and 5l (dashed bonds).

Table 2.  In vitro anti-HIV-1^a and HIV-2^b of some new sulphonamide derivatives.

Compound	Virus strain	EC50 (µg/mL)^c	CC50 (µg/mL)^d	SI^e
5a	IIIB	>59.58	59.58	<1
	ROD	>59.58	59.58	<1
5b	IIIB	>75.33	75.33	<1
	ROD	>75.33	75.33	<1
5c	IIIB	>70.80	70.80	<1
	ROD	>70.80	70.80	<1
5d	IIIB	>27.93	27.93	<1
	ROD	>27.93	27.93	<1
5e	IIIB	>65.63	>65.63	<1
	ROD	>65.63	>65.63	<1
5f	IIIB	>12.33	>12.33	<1
	ROD	>12.33	>12.33	<1
5g	IIIB	>58.75	58.75	<1
	ROD	>58.75	>58.75	<1
5h	IIIB	>14.08	14.08	<1
	ROD	>14.08	14.08	<1
5i	IIIB	>30.48	30.48	<1
	ROD	>30.48	30.48	<1
5j	IIIB	>11.75	11.75	<1
	ROD	>11.75	11.75	<1
5k	IIIB	>11.50	≥11.50	<orX1
	ROD	>11.50	≥11.50	<orX1
5l	IIIB	>13.00	13.00	<1
	ROD	>13.00	13.00	<1
5m	IIIB	>12.67	12.67	<1
	ROD	>12.67	12.67	<1
5n	IIIB	>12.30	12.30	<1
5o	ROD	>12.30	>12.30	<1
	IIIB	>13.65	13.65	<1
	ROD	>13.65	13.65	<1
5p	IIIB	>11.88	11.88	<1
	ROD	>11.88	11.88	<1
5q	IIIB	>11.67	11.67	<1
	ROD	>11.67	11.67	<1
5r	IIIB	>82.10	82.10	<1
	ROD	>82.10	82.10	<1
5s	IIIB	>90.83	90.83	<1
	ROD	>90.83	90.83	<1
5t	IIIB	>99.40	99.40	<1
	ROD	>99.40	99.40	<1
6a	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6b	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6c	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
6d	IIIB	>125.00	>125.00	X1
	ROD	>125.00	>125.00	X1
Nevirapine	IIIB	0.050	>4.00	>80
	ROD	>4.00	>4.00	<1
DDN/AZT	IIIB	0.0022	>25.00	>11587
	ROD	0.00094	>25.00	>26731

^aAnti-HIV-1 activity measured with strain III_B.

^bAnti-HIV-2 activity measured with strain ROD.

^cCompound concentration required to achieve 50% protection of MT-4 cells from the HIV-1- and 2-induced cytopathogenic effect.

^dCompound concentration that reduces the viability of mock-infected MT-4 cells by 50%.

^eSI, selectivity index (CC₅₀/EC₅₀).

Table 3.  Calculated value of descriptors.

Compound	LogP	P	V	S	EHOMO	ELUMO	ΔE	Etotal	μ	Binding energy	ΔΗ
75a	5.22	38.32	1095.9	611.90	−9.212	−0.995	8.217	−96002.3	4.015	−4719.94	−3.506
5b	6.01	40.95	1153	655.55	−9.32	−1.148	8.172	−103797.2	3.618	−4686.4	4.667
5c	5.36	38.23	1100.28	622.88	−9.366	−1.041	8.325	−105798.6	3.618	−4728.1	−44.92
5d	5.73	40.25	1130.56	645.94	−9.307	−1.013	8.294	−102950.7	3.508	−4701.0	−7.722
5e	5.27	38.42	1080.49	604.01	−9.321	−1.053	8.268	−99197.7	2.869	−4416.13	2.092
5f	6.06	41.04	1140.28	646.91	−9.418	−1.103	8.315	−107293.0	2.378	−4382.95	9.907
5g	5.41	38.33	1194.81	612.75	−9.423	−1.187	8.236	−109297	3.048	−4427.84	−42.831
5h	5.78	40.35	1129.09	637.29	−9.351	−1.174	8.177	−106451	3.189	−4402.25	−7.135
5i	5.20	44.99	1253.95	704.06	−8.956	−1.018	7.938	−107184.3	5.653	−5335.2	−2.178
5j	6.00	47.62	1310.64	746.42	−9.006	−1.046	7.96	−114977.57	5.4	−5300.0	7.649
5k	5.34	44.90	1258.38	714.86	−9.016	−1.053	7.963	−116980.66	5.516	−5343.4	−43.638
5l	5.72	46.92	1292.59	738.48	−9.008	−1.022	7.986	−114133.02	5.37	−5316.6	−6.766
5m	5.25	45.09	1243.09	698.25	−8.976	−1.099	7.877	−110681.36	4.649	−5033.0	1.768
5n	6.05	47.71	1299.70	739.96	−9.022	−1.053	7.969	−118474.66	4.176	−4997.9	11.562
5o	5.39	45.00	1249.18	708.36	−9.028	−1.147	7.881	−120477.72	4.197	−5041.3	−39.694
5p	5.77	47.02	1281.97	731.12	−9.019	−1.123	7.896	−117630.32	4.23	−5014.7	−3.060
5q	6.90	47.98	1304.85	679.53	−9.169	−0.964	8.205	−113803.33	4.063	−5924.5	25.629
5r	7.69	50.61	1360.85	725.56	−9.312	−0.994	8.318	−121597.32	3.473	−5890.1	34.726
5s	7.04	47.89	1309.33	692.79	−9.34	−0.979	8.361	−123599.93	3.657	−5933.0	−16.071
5t	7.42	49.91	1342.96	716.71	−9.292	−0.945	8.347	−120752.32	3.463	−5906.3	20.758

Binding energy in kcal/mol and heat of formation ΔH in kcal/mol of given series of compounds.

Energy difference (ΔE) in (eV); dipole moments (Δ) in Debye; frontier molecular orbitals energies (E_HOMO and E_LUMO); molecular surface (S); molecular volume (V); partition coefficient (LogP); polarizability (P); total energy E_total in kcal/mol.

Table 4.  Mulliken charges of the selected atoms.

Compound	Mulliken charges
	S1	O2	O3	N4	C5	C6	O7	C8	N9	N10	S11	C12
5a	2.252	−0.821	−0.845	−0.498	0.094	−0.032	−0.072	−0.133	−0.119	−0.072	0.169	−0.094
5b	2.245	−0.823	−0.845	−0.487	0.089	−0.027	−0.072	−0.134	−0.116	−0.073	0.172	0.099
5c	2.245	−0.823	−0.846	−0.486	0.089	−0.026	−0.072	−0.134	−0.113	−0.074	0.178	−0.105
5d	2.245	−0.823	−0.846	−0.486	0.089	−0.026	−0.072	−0.134	−0.113	−0.074	0.178	−0.105
5e	2.246	−0.823	−0.842	−0.489	0.089	−0.029	−0.071	−0.136	−0.110	−0.074	0.178	−0.103
5f	2.246	−0.824	−0.841	−0.491	0.088	−0.027	−0.070	−0.137	−0.109	−0.073	0.180	−0.108
5g	2.250	−0.828	−0.836	−0.498	0.091	−0.030	−0.075	−0.141	−0.100	−0.073	0.166	−0.098
5h	2.247	−0.829	−0.834	−0.501	0.091	−0.033	−0.072	−0.135	−0.113	−0.069	0.169	−0.097
5i	2.262	−0.818	−0.841	−0.513	0.099	−0.034	−0.069	−0.129	−0.124	−0.075	0.173	−0.096
5j	2.262	−0.819	−0.840	−0.512	0.096	−0.029	−0.071	−0.132	−0.119	−0.074	0.183	−0.109
5k	2.260	−0.819	−0.840	−0.509	0.095	−0.029	−0.071	−0.132	−0.118	−0.073	0.181	−0.104
5l	2.260	−0.820	−0.841	−0.508	0.094	−0.029	−0.073	−0.131	−0.118	−0.072	0.180	−0.104
5m	2.249	−0.819	−0.838	−0.493	0.087	−0.031	−0.072	−0.128	−0.121	−0.074	0.171	−0.093
5n	2.251	−0.820	−0.838	−0.495	0.086	−0.027	−0.073	−0.131	−0.116	−0.073	0.182	−0.108
5o	2.253	−0.820	−0.837	−0.497	0.087	−0.027	−0.074	−0.131	−0.115	−0.073	0.180	−0.102
5p	2.253	−0.820	−0.838	−0.497	0.087	−0.029	−0.073	−0.131	−0.116	−0.072	0.180	−0.103
5q	2.251	−0.821	−0.844	−0.499	0.082	−0.025	−0.070	−0.132	−0.119	−0.073	0.167	−0.093
5r	2.252	−0.822	−0.842	−0.502	0.080	−0.019	−0.064	−0.141	−0.106	−0.077	0.176	−0.108
5s	2.251	−0.822	−0.842	−0.500	0.077	−0.018	−0.066	−0.141	−0.104	−0.077	0.175	−0.105
5t	−2.249	−0.822	−0.842	−0.499	0.077	−0.017	−0.065	−0.143	−0.101	−0.078	0.174	−0.106

Table 5.  Observed and calculated anti-HIV activity (EC₅₀) of given series of compounds.

Compound	Observed EC50	Calculated EC50
		Model-5	Model-6	Model-7	Model-8
5a	59.58	29.15748	40.01327	35.615	39.79637
5b	75.33	45.87267	37.56644	54.21975	50.27844
5c	70.80	88.92503	88.07061	96.79234	90.84148
5d	27.93	60.99637	68.70131	72.74313	65.39883
5e	65.63	70.53132	73.86845	82.64822	80.77886
5g	58.75	81.71542	54.0463	82.87232	81.30566
5h	14.08	18.78503	14.21674	19.24086	20.83762
5i	30.48	24.88479	25.41575	28.34484	29.27171
5j	11.75	18.13093	16.7519	20.8732	19.34272
5k	11.50	17.96007	16.52532	19.16386	19.09697
5l	13.00	11.702	11.35492	12.39915	12.21044
5m	12.67	18.77293	16.75089	22.12425	21.56269
5n	12.30	13.18797	13.03788	16.12007	13.70624
5o	13.65	16.59495	13.36934	19.46695	17.04569
5p	11.88	10.93604	9.004799	12.54827	11.20977
5q	11.67	18.95501	20.71958	21.57613	29.96061
5r	82.10	75.44735	61.08112	85.12498	86.30384
5s	90.83	105.547	85.42559	108.8894	117.8449
5t	99.40	97.89804	89.67306	112.2172	111.0916

Figure 4.  A plot between observed activity and calculated activity for 5, 6, 7, and 8 models. (A) Model-5: r = 0.89286. (B) Model-6: r = 0.86842. (C) Model-7: r = 0.90299. (D) Model-8: r = 0.91162.

Scheme 1.  Reagents and conditions. (i) 4-Chloromethyl/methylbenzenesulphonyl chlorides, K₂CO₃, CHCl₃; (ii) MeOH, H₂SO₄, reflux 4 h; (iii) N₂H₄.H₂O, MeOH, reflux 3–4 h; (iv) CS2, KOH, MeOH, reflux 18–20 h; (v) 1.0 eq. YCH₂C₆H₄X, acetone, K₂CO₃, r.t.; (vi) 2.0 eq. YCH₂C₆H₄X, acetone, K₂CO₃, r.t.