Insights through AM1 calculations into the structural requirement of N-hydroxythiosemicarbazone analogs as anti-tubercular agents

Figures & data

Table I.  Structure and activity of N-hydroxythiosemicarbazone analogs.

Comd. No.	R	R1	MIC^*	pMIC^†
1	H	H	64.02	4.194
2	H	2-OH	29.58	4.529
3	H	4-OH	29.58	4.529
4	H	4-N(CH3)2	52.45	4.280
5	H	4-OCH3	14.95	4.825
6	H	4-CH3	12.97	4.887
7	H	3-OCH3,4-OH	27.21	4.565
8	H	4-Cl	13.02	4.885
9	H	4-NO2	6.49	5.188
10	H	2-NO2	6.49	5.188
11	CH3	H	14.95	4.825
12	CH3	2-OH	13.89	4.857
13	CH3	4-CH3	6.98	5.156
14	CH3	4-Cl	3.2	5.495
15	CH3	4-NO2	0.78	6.108
16	C6H5	4-Br	0.28	6.553
17	–	H	64.02	4.194
18	–	F	24.58	4.609

* Minimum inhibitory concentration in μM against Mycobacterium tuberculosis H37Rv.

^† Negative logarithm of minimum inhibitory concentration in mole

Table II.  Fujita-Ban matrix of N-hydroxythiosemicarbazone analogs with calculated (Cal) value.

		R						R1
Comp. No.	μ^*	CH3	C6H5	2-OH	2-NO2	3-OCH3	4-OH	4-N(CH3)2	4-OCH3	4-CH3	4-Cl	4-NO2	4-Br	Calc pMIC^†
1	1	0	0	0	0	0	0	0	0	0	0	0	0	4.631
2	1	0	0	1	0	0	0	0	0	0	0	0	0	4.631
3	1	0	0	0	0	0	1	0	0	0	0	0	0	4.631
4	1	0	0	0	0	0	0	1	0	0	0	0	0	4.631
5	1	0	0	0	0	0	0	0	1	0	0	0	0	4.631
6	1	0	0	0	0	0	0	0	0	1	0	0	0	4.631
7	1	0	0	0	0	1	1	0	0	0	0	0	0	4.631
8	1	0	0	0	0	0	0	0	0	0	1	0	0	4.631
9	1	0	0	0	0	0	0	0	0	0	0	1	0	5.395
10	1	0	0	0	1	0	0	0	0	0	0	0	0	4.631
11	1	1	0	0	0	0	0	0	0	0	0	0	0	5.135
12	1	1	0	1	0	0	0	0	0	0	0	0	0	5.135
13	1	1	0	0	0	0	0	0	0	1	0	0	0	5.135
14	1	1	0	0	0	0	0	0	0	0	1	0	0	5.135
15	1	1	0	0	0	0	0	0	0	0	0	1	0	5.900
16	1	0	1	0	0	0	0	0	0	0	0	0	1	6.553

* μ is the value for core nucleus used in Fujita-Ban analysis

^† Calculated pMIC considering Equation (1).

Table III.  Value of substituent constant and Hansch analysis data of calculated, calculated (loo), residual and Z-score of N-hydroxythiosemicarbazone analogs.

	Substituent Constant				Model-2 (pMIC)
Comd. No.	MR1	σ1	Fhyd	Cal^*	Calres^†	Z-score	Cal(loo)^‡	Cal(loo)res^¶
1	1.03	0.00	0.23	4.414	− 0.221	− 1.192	4.480	− 0.287
2	2.85	0.12	0.23	4.598	− 0.069	− 0.372	4.609	− 0.080
3	2.85	− 0.37	0.23	4.208	0.321	1.733	4.102	0.427
4	15.35	− 0.83	0.23	4.447	− 0.166	− 0.899	4.768	− 0.488
5	7.87	− 0.27	0.23	4.530	0.295	1.594	4.485	0.340
6	5.65	0.10	0.23	4.717	0.170	0.917	4.701	0.186
7	10.72	− 0.25	0.23	4.684	− 0.119	− 0.642	4.714	− 0.149
8	6.03	0.23	0.23	4.839	0.046	0.250	4.834	0.051
9	7.36	0.78	0.23	5.341	− 0.153	− 0.826	5.416	− 0.229
10	7.36	0.71	0.23	5.285	− 0.097	− 0.525	5.325	− 0.137
11	1.03	0.00	0.77	4.923	− 0.098	− 0.527	4.956	− 0.130
12	2.85	0.12	0.77	5.106	− 0.249	− 1.345	5.149	− 0.292
13	5.65	0.10	0.77	5.226	− 0.070	− 0.376	5.233	− 0.077
14	6.03	0.23	0.77	5.348	0.147	0.796	5.333	0.161
15	7.36	0.78	0.77	5.849	0.259	1.397	5.754	0.354
16	8.88	0.23	1.90	6.549	0.003	0.018	6.540	0.013

* Calculated data of the compounds using model

^† Residual value of calculated data

^‡ Calculated (loo) data of the compounds using leave-one-out method

^¶ Residual value of calculated (loo) data.

Figure 1.  Plot of calculated (loo) MIC against observed MIC by models 2, 3 and 4.

Table IV.  Calculated, calculated (loo), residual and Z-score of N-hydroxythiosemicarbazone analogs obtained from model-3 and model-4.

	Model-3 (pMIC)					Model-4 (pMIC)
Comd. No.	Cal^*	Calres^†	Z-score	Cal(loo)^‡	Cal(loo)res^¶	Cal^*	Calres^†	Z-score	Cal(loo)^‡	Cal(loo)res^¶
1	4.457	− 0.264	− 1.373	4.549	− 0.356	4.228	− 0.034	− 0.200	4.236	− 0.042
2	4.608	− 0.079	− 0.410	4.617	− 0.088	4.502	0.027	0.157	4.499	0.030
3	4.855	− 0.326	− 1.698	4.901	− 0.372	4.522	0.007	0.043	4.521	0.008
4	4.506	− 0.225	− 1.174	4.794	− 0.514	4.434	− 0.153	− 0.890	5.250	− 0.970
5	4.816	0.009	0.047	4.816	0.010	4.588	0.237	1.374	4.568	0.258
6	4.529	0.358	1.863	4.480	0.407	4.577	0.310	1.799	4.538	0.349
7	4.697	− 0.132	− 0.687	4.736	− 0.171	4.818	− 0.253	− 1.467	4.842	− 0.277
8	4.890	− 0.004	− 0.022	4.890	− 0.005	4.791	0.094	0.547	4.782	0.104
9	5.375	− 0.187	− 0.972	5.412	− 0.224	4.889	0.299	1.735	4.863	0.325
10	4.958	0.230	1.199	4.924	0.264	5.080	0.108	0.624	5.069	0.118
11	4.707	0.118	0.614	4.678	0.147	4.915	− 0.089	− 0.519	4.928	− 0.103
12	5.018	− 0.161	− 0.837	5.032	− 0.174	5.120	− 0.263	− 1.523	5.147	− 0.290
13	4.932	0.225	1.169	4.895	0.262	5.354	− 0.198	− 1.149	5.397	− 0.241
14	5.331	0.163	0.851	5.302	0.192	5.469	0.026	0.153	5.464	0.031
15	6.111	− 0.003	− 0.016	6.112	− 0.004	6.108	0.000	0.001	6.108	0.000
16	6.494	0.059	0.307	6.416	0.137	6.487	0.066	0.382	6.359	0.194
17	3.993	0.201	1.044	3.907	0.287	4.374	− 0.180	− 1.043	4.438	− 0.245
18	4.591	0.018	0.095	4.582	0.028	4.614	− 0.004	− 0.025	4.616	− 0.006

* Calculated data of the compounds using model

^† Residual value of calculated data

^‡ Calculated (loo) data of the compounds using leave-one-out method

^¶ Residual value of calculated (loo) data.

Table V.  Comparative statistics of QSAR models obtained from Hansch substituent constant (Model-2), topological descriptors (Model-3) and conformational dependent descriptors (Model-4).

Statistical Parameter	Model-2	Model-3	Model-4
n	16	18	18
r	0.955	0.951	0.961
	0.891	0.885	0.907
SEE	0.207	0.212	0.190
F	41.802	44.575	56.459
Fmax	9.831	29.308	54.092
FIT	5.016	4.952	6.273
QF	4.616	4.495	5.059
PE	0.015	0.015	0.012
AIC	0.071	0.070	0.057
ICAP	< 0.239	< 0.434	< 0.556
	0.875	0.895	0.929
Sbs	0.079	0.105	0.065
Chance	< 0.001	< 0.001	< 0.001
q^2	0.828	0.832	0.760
SPRESS	0.290	0.282	0.337
SDEP	0.251	0.248	0.297
q2(nout)*	–	0.821	0.781
SPRESS(nout)	–	0.266	0.314
SDEP(nout)	–	0.256	0.302
VIF of Descriptors	< 1.111	< 1.981	< 2.051

* In leave n out method, value of n is three.

Figure 2.  Illustrative representation of N-hydroxythiosemicarbazones interaction with receptor.